Cardiovascular

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Embryology CVS
Embryonic Structure Gives RISE TO:
• Truncus arteriosus → Ascending aorta and pulmonary trunk.

• Bulbus cordis → Smooth parts (outflow tract) of left and right ventricles.
• Primitive ventricle → Trabeculated part of left and right ventricles
• Primitive atrium → Trabeculated part of left and right atria
• Primitive pulmonary vein → Smooth part of left atrium
• Left horn of sinus venosus → Coronary sinus.
• Right horn of sinus venosus → Smooth part of right atrium (sinus venarum).
Dr/Ahmed Shebl
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https://t.me/USMLEEndopoint USMLE Endpoint
Cardinal Veins:
• Form SVC/IVC (not from heart tube) → connect to right atrium.
• Superior vena cava → R common cardinal vein and R anterior cardinal vein.
• Inferior vena cava → Posterior subcardinal, and supracardinal veins.
• Venous system of the developing embryo:
➢ Vitelline veins → veins of the portal system.
➢ Umbilical → degenerate.
➢ Cardinal veins → veins of the systemic circulation e.g. SVC.
Heart morphogenesis:
• First functional organ in vertebrate embryos; beats spontaneously by week 4 of development.
Cardiac looping:
• Primary heart tube loops to establish left-right polarity; begins in week 4 of gestation.
• Establishes left-right orientation in chest.
• Requires cilia and dynein.
• Defect in left-right dynein (involved in L/R asymmetry) can lead to dextrocardia, as seen in
Kartagener syndrome (primary ciliary dyskinesia).
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Septation of the chambers:

Atrial septation
1. Septum primum grows toward endocardial cushions, narrowing foramen primum.
2. Foramen secundum forms in septum primum (foramen primum disappears).
3. Septum secundum develops as foramen secundum maintains right-to-left shunt.
4. Septum secundum expands and covers most of the foramen secundum. The residual foramen
is the foramen ovale.
5. Remaining portion of septum primum forms valve of foramen ovale.
6. Septum secundum and septum primum fuse to form the atrial septum.
7. Foramen ovale usually closes soon after birth because of → LA pressure.
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Patent foramen ovale:

• Caused by failure of septum primum and septum secundum to fuse after birth.
• Considered normal variant in adults (20-30%). Most are left untreated.
• Can lead to paradoxical emboli (venous thromboemboli that enter systemic arterial
circulation), similar to those resulting from an ASD.
• Remains closed as pressure in LA > RA → so, ↑RA pressure → RT to LT shunt →
hypoxemia.
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Septation of the Ventricles:
1. Muscular ventricular septum forms. Opening is called interventricular foramen.

2. Aorticopulmonary septum rotates and fuses with muscular ventricular septum to form
membranous interventricular septum, closing interventricular foramen.
3. Growth of endocardial cushions separates atria from ventricles and contributes to both
atrial septation and membranous portion of the interventricular septum.
4. Ventricular Septum Pathology:
a. Membranous VSD (most common type)
b. Muscular VSD
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Endocardial Cushions
• Contribute to several cardiac structures:
▪ Atrial septum
▪ Ventricular septum
▪ AV valves (mitral/tricuspid)
▪ Semilunar valves (aortic/pulmonic)
• Endocardial cushion defects:
▪ Atrioventricular canal defects.
▪ Atrioventricular septal defects
▪ ASD, VSD, Valvular malformations
▪ Common in Down syndrome.
• UW: congenital MR + ostium primum ASD → endocardial cushion defect → mostly with
Down syndrome.
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Aorticopulmonary septum: (Spiral Septum)

• Formed from neural crest cells → formation of truncal and bulbar ridges that spiral and
fuse to form aorticopulmonary septum.
• Separates aorta and pulmonary arteries.
• Fuses with interventricular septum.
Abnormal AP septum (conotruncal abnormalities):

1. Transposition of great vessels: Failure to spiral.
2. Tetralogy of Fallot:
a. Skewed septum development → Anterosuperior displacement of septum.
b. Abnormal neural crest cell migration.
3. Persistent truncus arteriosus: Partial/incomplete septum develop.
Valve development:
<
• Aortic/pulmonary: derived from endocardial cushions of outflow tract.

• Mitral/tricuspid: derived from fused endocardial cushions of the AV canal.
• Valvular anomalies may be stenotic, regurgitant, atretic (e.g., tricuspid atresia), or displaced
(e.g., Ebstein anomaly).
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Shunts
• Left side pressures >> Right side pressures.
• Shunts → Left to right flow:
➢ VSD (LV → RV)
➢ ASD (LA → RA)
➢ PDA (Aorta → Left pulmonary artery)
• At birth:
➢ Left to right flow → volume overload of right heart.
➢ Blood flow to lungs unimpaired → no cyanosis.
• YEARS later (untreated):
➢ Pulmonary vessels become stiff/thick.
➢ Right ventricle hypertrophies.
➢ Right sided pressures rise.
➢ Shunt reverses (now R → L).
➢ Cyanosis occurs (Eisenmenger syndrome) → “Blue kids” not “blue babies”.
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Congenital heart diseases
Right-to-left shunts (cyanotic heart diseases)

• Early cyanosis “blue babies.”
• Often diagnosed prenatally or become evident immediately after birth.
• Usually require urgent surgical treatment and/or maintenance of a PDA.
1- Persistent truncus arteriosus

• Truncus arteriosus fails to divide into pulmonary trunk and aorta due to lack of
aorticopulmonary septum formation (neural crest derivative).
• Most patients have accompanying VSD.
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2- Transposition of great vessels
• Due to failure of the aorticopulmonary septum to spiral.
• Aorta leaves RV (anterior) and pulmonary trunk leaves LV (posterior) → separation of
systemic and pulmonary circulations.
• Not compatible with life unless a shunt is present to allow mixing of blood (eg, VSD, PDA,
or patent foramen ovale).
• Without surgical intervention, most infants die within the first few months of life.
• High incidence in infants of diabetic mothers.
3- Tricuspid atresia
• Absence of tricuspid valve and hypoplastic RV.
• Requires both ASD and VSD for viability.
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4- Tetralogy of Fallot (T4)
• Caused by anterosuperior displacement of the infundibular septum.
• Most common cause of early childhood cyanosis.
• Pathophysiology:
1- Septum displaced (moves toward RV):
▪ Causes “overriding aorta” → 5-95% of aorta may lie over RV
▪ Causes VSD → Usually large (“non-restrictive”)
2- Infundibulum “Conus Arteriosus”:
▪ “Funnel” leading to pulmonic valve
▪ Develops from bulbus cordis → smooth, muscular structure at RV outflow to
PA.
3- “Infundibular stenosis”
▪ Subpulmonary stenosis → RV outflow tract obstruction.
▪ Abnormal pulmonary valve → Rarely main cause of obstruction
▪ Flow obstruction → RVH
• Components:
1- Pulmonary infundibular stenosis:
▪ Most important determinant for prognosis.
▪ Pulmonary stenosis forces right-to-left flow across VSD → RVH, “tet spells”
(often caused by crying, fever, and exercise due to exacerbation of RV
outflow obstruction).
2- Right ventricular hypertrophy (RVH)— boot-shaped heart on CXR
3- Overriding aorta
4- VSD
▪ Squatting: ↑ SVR, ↓ right-to-left shunt, improves cyanosis.
• Treatment: early surgical correction.
• Boot-shaped heart:
▪ Adult → RVH
▪ Infant → T4
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USMLE Endpoint
5- Total anomalous pulmonary venous return

• Pulmonary veins drain into right heart circulation (SVC, coronary sinus, etc).
• Associated with ASD and sometimes PDA to allow for right-to-left shunting to maintain CO.
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6- Ebstein anomaly
• Characterized by displacement of tricuspid valve leaflets downward into RV, artificially
“atrializing” the ventricle.
• Can be caused by lithium exposure in utero.
• C/P:
▪ Tricuspid regurge → right sided HF.
▪ Dilated RA → ↑ risk of SVT.
▪ Accessory conduction pathways → WPW syndrome.
7- Complete AV canal defect:

• AV canal contributes to the formation of the AV valves (ie, mitral and tricuspid valves) and
the AV septum.
• Complete absence → single common AV valve, which is often associated with regurgitation.
• Strong association with down syndrome.
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Right to left shunts (Acyanotic heart diseases)

• Acyanotic at presentation; cyanosis may occur years later.
1- Ventricular Septal Defect (VSD)

• Most common congenital anomaly.
• Communication LV/RV → harsh, holosystolic murmur → Tricuspid area (LLSB).
• O2 saturation increases in RV and pulmonary artery.
• Characterized in many ways: • Size • Location • Associated defects.
• Small VSD:
➢ Resists flow across defect (“restrictive”) → lots of turbulence → loud murmur.
• Large VSD:
➢ Large hole (“non-restrictive”) → significant shunting.
➢ May lead to LV overload and HF → often closed surgically.
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USMLE Endpoint
2- Atrial septal defect (ASD)
• Communication between left/right atrium → adds volume to RA/RV.
• Type of murmurs associated:
➢ Delays closure of pulmonic valve → wide, fixed splitting of S2.
➢ Increased flow across PV/TV → systolic ejection murmur.
➢ Rarely a mid-diastolic murmur
• O2 saturation increases in RA, RV, and pulmonary artery.
• May lead to paradoxical emboli (systemic venous emboli use ASD to bypass lungs and
become systemic arterial emboli).
Secundum type ASD:

• Most common.
• Defects at site of foramen ovale/ostium secundum:
➢ Poor growth of secundum septum
➢ Or excessive absorption of primum septum
• Located mid-septum.
• Often isolated defect.
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USMLE Endpoint
• Patent foramen ovale Vs. ASD:
▪ PFO → failure of fusion of septum primum and septum secundum.
▪ Secundum ASD → defect in primitive atrium.
Primum type ASD
• Failure of the septum primum to fuse completely with the endocardial cushions leaves a
persistent ostium primum.
• Located near AV valves (the lower part of the interatrial septum).
• Often occurs with other defects.
• These patients usually also have:
➢ Cleft in the anterior leaflet of the mitral valve as well as in the septal leaflet of the
tricuspid valve, causing regurgitation through the AV valves.
• Seen in endocardial cushion defects (Down syndrome).
3- Patent ductus arteriosis
• Ductus arteriosus shunts blood in utero: Left pulmonary artery → aorta.

• Closes close after birth:
➢ “Functional” closure 18 to 24 hours (smooth muscle)
➢ “Anatomic” occlusion over next few days/weeks
• Becomes ligamentum arteriosum.
• Patency maintained by prostaglandin E2 (major source in utero is placenta).
➢ Alprostadil:
▪ Prostaglandin E1 → maintains patency of ductus arteriosus.
▪ Key effect: delivers blood to lungs.
▪ Useful when poor RV → PA blood flow
• Tetralogy of Fallot
• Pulmonary atresia
➢ Indomethacin:
▪ NSAID that inhibits cyclooxygenase → decreases prostaglandin formation.
▪ Can be used to close PDA.
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• PDA is associated with congenital rubella syndrome:
➢ Mother: Rash, fever, lymphadenopathy.
➢ Baby: Deafness, cataracts, cardiac disease (PDA common).
➢ Rare in developed countries (vaccination).
➢ Consider in infants whose mothers are immigrants.
• Uncorrected PDA can cause differential cyanosis:
➢ Occurs when shunt reverses R → L
➢ Blue toes, normal fingers
4- Eisenmenger’s Syndrome
• Uncorrected ASD/VSD/PDA → Right heart chronically overloaded → RV Hypertrophy →
Pulmonary hypertension.
• Shunt reverses right >> left (bypassing lung).
▪ Cyanosis, Clubbing, Polycythemia (very high Hct).
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Coarctation of aorta
• Aortic narrowing near insertion of ductus arteriosus (“juxtaductal”).
• Subtypes based on location of ductus arteriosus.
Preductal or Infantile type:

• Symptoms varies according the patency of ductus arteriosus:
• Open ductus arteriosus: (at birth)
➢ Ductus arteriosus supplies lower extremities.
➢ Deoxygenated blood to lower extremity → lower extremity cyanosis may occur.
• Ductus closure:
➢ All flow through aorta with severe narrowing → abrupt increase afterload.
➢ Rise in LVEDP → Acute heart failure.
➢ LV can dilate → fail → shock.
➢ Poor development of collateral vessels.
• Key associations: Turner syndrome (45, XO).
Postductal or Adult type:

• Ductus arteriosus does not supply lower extremities
• Collaterals develop.
• May go undetected until adulthood.
• Lower extremities → low blood pressure → ↑ Renin release → Salt/water retention →
Vasoconstriction (AII) → Weak pulses (“brachio-femoral delay”)
• Upper extremities and head → high blood pressure → Secondary hypertension.
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Associations of coarctation
1. Bicuspid aortic valve:
a. Found in up to 60% of coarctation cases.
b. The most common associated anomaly with turner.
c. Early systolic + high frequency click over the apex.
d. Can be present also with AR murmur.
e. Associated with premature calcification at the 6th decade (normally aortic valve
calcification occurs at 8th to 9th decades) → aortic stenosis.
f. Most common cause of congenital aortic stenosis is calcification of bicuspid aortic
valve.
g. NB: Coarctation + murmur → AR d2 bicuspid aortic valve.
2. Intracranial aneurysms: Occur in about 10% of patients with coarctation.
3. Turner syndrome.
Signs and symptoms of coarctation of aorta

• Hypertension in upper extremities.
• Weak delayed pulse in lower extremities (brachial-femoral delay).
• Murmur over back between scapula.
• With age, intercostal arteries enlarge due to collateral circulation; arteries erode ribs →
notched ribs on CXR.
• 3‐sign: Bulge before and after coarctation on chest x-ray.
Complications of coarctation of aorta

• HF: pressure overload on the LV.
• ↑ Risk of cerebral hemorrhage (berry aneurysms).
• Aortic rupture/ dissection.
• Endocarditis/endarteritis:
➢ High-low pressure across narrowing → Endothelial injury.
➢ Low pressure distal to narrowing → Bacteria may attach more easily.
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• UW: Differential clubbing and cyanosis:
▪ Without blood pressure or pulse discrepancy are pathognomonic for a large patent
ductus arteriosus complicated by Eisenmenger syndrome (reversal of shunt flow
from left-to-right to right-to-left).
▪ With BP or pulse discrepancy → Severe preductal coarctation of the aorta.
Congenital heart disease associations
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Fetal erythropoiesis
,
• Fetal erythropoiesis occurs in:

▪ Yolk sac (3–8 weeks)
▪ Liver (6 weeks–birth)
▪ Spleen (10–28 weeks)
▪ Bone marrow (18 weeks to adult)
▪ Young Liver Synthesizes Blood.
Hemoglobin development
• Embryonic globins: ζ and ε.
• Fetal hemoglobin (HbF) = α2γ2.
• Adult hemoglobin (HbA) = α2β2.
• NB: HbF has higher affinity for O2 due to less avid binding of 2, 3-BPG, allowing HbF to
extract O2 from maternal Hemoglobin HbA1 and HbA2) across the placenta.
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Fetal circulation
➢ UW: the highest value of O2 saturation is recorded in IVC in fetal circulation. As it carries
oxygenated blood from umbilical veins.
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Fetal-postnatal derivatives
Ligamentum teres:
• Remnant of umbilical vein.
• Lies within the free edge of the darker falciform ligament, which attaches the liver to both
the diaphragm and the anterior abdominal wall.
• Divides the anatomic left and right lobes of the liver and easily seen as a darker structure
on CT because it contains some fat.
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ANATOMY OF CVS
Anterior-Posterior Structures
• Right ventricle → Anterior:
✓ Injured if penetrating trauma at the mid and lower-left sternal border.
✓ The parietal pleura would be injured as well, but the left lung itself would not be
punctured as there is no middle lobe on the left side, and the superior lobe of the left lung is
displaced laterally by the cardiac impression.
• Left atrium → Posterior.
✓ Enlargement can cause dysphagia (due to compression of the esophagus) or hoarseness (due
to compression of the left recurrent laryngeal nerve, a branch of the vagus nerve).
✓ The closest to the probe of transesophageal ECHO.
✓ If the probe is placed posterior → descending aorta will be faced.
✓ The left atrial appendage is particularly susceptible to thrombus formation.
• Left ventricle → the left lateral aspect of the heart.
✓ A stab wound angled slightly medially in the fourth intercostal space at the midclavicular
line could strike the left ventricle, but only after passing through the bulk of the left lung.
• Right atrium → right border of the heart.
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Surface anatomy of the heart:

• 2×3=6 + apex
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Anatomy of the conduction system
Anatomy of the AV node

• Location:
▪ The AV node is located on the endocardial surface of the right atrium, near the
insertion of the septal leaflet of the tricuspid valve and the orifice of the coronary
sinus.
• Radiofrequency ablation:
▪ Performed in patients with arrhythmia who do not respond to pharmacologic therapy.
▪ Locations:
▪ To the AV node is occasionally.
▪ Another area frequently involved in atrial fibrillation pathogenesis is the opening of
the pulmonary veins in the left atrium; this area is often a target for radiofrequency
ablation, but it is not where the AV node is located.
Anatomy of the SA node

• Located in the upper anterior right atrium at the opening of the superior vena cava.
Biventricular peacemaker of the heart

• A device that requires 2 or 3 leads:
▪ If 3 leads are used, the first 2 are placed in the right atrium and right ventricle.
▪ The third lead is used to pace the left ventricle.
• Right atrial and ventricular leads:
▪ Easy to place as they only need to traverse the left subclavian vein and superior vena
cava to reach these cardiac chambers.
• Left ventricular lead:
▪ More difficult to position. The preferred transvenous approach involves passing the
left ventricular pacing lead from the right atrium into the coronary sinus, which
resides in the atrioventricutar groove on the posterior aspect of the heart it is then
advanced into one of the lateral venous tributaries in order to optimize left
ventricular pacing.
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• UW: coronary sinus:

▪ Venous drainage of the heart.
▪ Opens in the RA and normally not seen by ECHO.
▪ So, coronary sinus dilatation → is d2 increase in the RT side pressure because of
pulmonary HTN.
Blunt aortic injury (traumatic aortic rupture)

• Mechanism:
✓ Sudden deceleration that results in extreme stretching and torsional forces affecting the heart
and aorta.
✓ Injury occurs most often at the aortic isthmus:
▪ Proximal descending aorta just distal to origin of left subclavian artery.
▪ which is tethered by the ligamentum arteriosum and is relatively fixed and immobile
compared to the adjacent descending aorta.
• Clinically:
✓ The majority (80%) of patients die from aortic rupture before reaching the hospital.
✓ Those who survive the initial injury have nonspecific findings such as chest pain, back pain,
or shortness of breath.
✓ A widened mediastinum may also be seen on chest x-ray.
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Coronary artery anatomy
• LAD supplies:
✓ Anterior surface of the LV.
✓ Anterior 2/3 of interventricular septum.
✓ Anterolateral papillary muscle.
✓ Most commonly occluded.
• PDA supplies:
✓ AV node (dependent on dominance).
▪ AV nodal artery arises from PDA (if rt dominant) or from LCX (if left dominant).
✓ Posterior 1/3 of interventricular septum.
✓ Posterior 2/3 walls of ventricles, and posteromedial papillary muscle.
✓ Right (acute) marginal artery supplies RV.
✓ Diaphragmatic surface of the heart (composed mainly from RV).
• RCA supplies:
✓ SA node (blood supply independent of dominance).
▪ Infarct may cause nodal dysfunction (bradycardia or heart block).
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• Dominance:
✓ Right-dominant circulation (85%) = PDA arises from RCA.
✓ Left-dominant circulation (8%) =PDA arises from LCX.
✓ Codominant circulation (7%) = PDA arises from both LCX and RCA.
• Coronary blood flow peaks in early diastole.

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• Papillary muscles of the mitral valve:
✓ Post. papillary muscle supplied only by PDA.
✓ Ant. papillary muscle has dual blood supply by LAD & LCX → less likely to rupture after
MI.
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• UW: The optimal site for obtaining vascular access in the lower extremity during cardiac
catheterization is the common femoral artery below the inguinal ligament. Cannulation above the
inguinal ligament can significantly increase the risk of retroperitoneal hemorrhage.
Pericardium:
• Consists of 3 layers (from outer to inner):
▪ Fibrous pericardium.
▪ Parietal layer of serous pericardium.
▪ Visceral layer of serous pericardium.
• Pericardial cavity lies between parietal and visceral layers.
▪ Accumulation of fluid in the pericardial cavity compresses the heart, resulting in cardiac
tamponade.
• Pericardium innervated by phrenic nerve.
▪ Pericarditis can cause referred pain to the neck, arms, or one or both shoulders (often left).
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CVS PHYSIOLOGY
Important Terms
• Stroke Volume (SV) = EDV -ESV

• Ejection Fraction (EF) = SV /EDV
• Cardiac Output (CO) = SV * HR
• Venous Return (VR)
▪ Blood returned to left ventricle
▪ Should be equal to the cardiac output
• Total peripheral resistance
▪ Resistance to blood flow from peripheral structures
▪ Vasoconstriction → ↑ TPR
▪ Vasodilation → ↓ TPR
• Systolic blood Pressure (SBP)
▪ Largely determined by stroke volume
• Diastolic blood Pressure (DBP)
▪ Largely determined by TPR
• Pulse pressure = SBP – DBP
▪ Proportional to SV
• Mean arterial pressure (MAP) = 2/3 DBP + 1/3 SBP
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Cardiac output
• More cardiac output = more work → more O2 demand
▪ CO = HR x SV
• Determinants of cardiac output:
▪ Stroke volume
▪ Contractility
▪ Preload
▪ Afterload
▪ Heart rate
• CO = rate of O2 consumption / arteriovenous O2 content difference.
▪ The rate of oxygen consumption can be determined with an oxygen meter by measuring the
rate of disappearance of oxygen in exhaled air.
Stroke volume
• Stroke Volume affected by Contractility, Afterload, and Preload.
• ↑ SV with:
1. Contractility (eg, anxiety, exercise).
2. ↓ Preload (eg, early pregnancy).
3. ↓ Afterload.
• A failing heart has ↓ SV (systolic and/or diastolic dysfunction).
Contractility
• How hard the heart muscle squeezes.
• Ejection fraction = index of contractility.
• Major regulator: sympathetic nervous system → also increases heart rate.
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To INCREASE contractility (and SV) To DECREASE contractility (and SV)
1. Catecholamine stimulation via β-1 1. β-1 blockade (↓ cAMP).

receptor: 2. HF with systolic dysfunction.
a. Ca2+channels phosphorylated → Ca2+ 3. Acidosis.
entry → Ca2+_induced Ca2+ release 4. Hypoxia/hypercapnia.
and ↑ Ca2+storage in sarcoplasmic 5. Non-dihydropyridine Ca2+channel blockers.
reticulum.
b. Phospholamban phosphorylation →
active Ca2+ATPase → ↑ Ca2+ storage
in sarcoplasmic reticulum.
2. ↑ Intracellular Ca2+
3. ↓ Extracellular Na+ (↓ activity of
Na+/Ca2+ exchanger).
4. Digitalis (blocks Na+/K+ pump → ↑
intracellular Na+ → ↓ Na+/Ca2+
exchanger activity → ↑ intracellular Ca2+)
Lusitropy:
• Myocardial relaxation.
• Mediated by SERCA.
1) SERCA is regulated by a protein called phospholamban (PLB).
▪ Phospholamban is an inhibitor to SERCA.
2) Sympathetic stimulation → phosphorylates PLB → ↓ PLB → ↑ SERCA → faster
relaxation → faster contraction.
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Preload
• Amount of blood loaded into left ventricle.
• Also, how much stretch is on fibers prior to contraction.
▪ Some books say “length” instead of “stretch”.
▪ More preload = more cardiac output.
▪ More preload = more work the heart must do → more O2 is required.
To INCREASE Preload To DECREASE Preload
1. Add volume (blood, IVF) 1. Remove volume (bleeding, dehydration)

2. Slow heart rate → more filling →more 2. Raise heart rate (opposite mechanism
volume above)
3. Constrict veins: 3. Pool blood in veins:
a. Veins force blood into heart a. Mechanism of action of nitrates
b. Veins hold LARGE blood volume b. Relieve angina
c. Response to blood loss → venous c. Lower preload → less work for heart
constriction
d. Sympathetic stimulation → α1
receptors in veins
• Important Terms:
▪ LVEDV: Volume of blood in the left ventricle when filled.
▪ LVEDP: Pressure in the left ventricle when filled.
Afterload
• Forces resisting flow out of left ventricle.
• Heart must squeeze to increase pressure.
• Needs to open aortic valve → push blood into aorta.
• This is harder to do if:
▪ Blood pressure is high
▪ Aortic valve is stiff
▪ Something in the way: HCM, sub-aortic membrane
To INCREASE Afterload To DECREASE Afterload
1. Raise mean blood pressure. 1. Lower the mean blood pressure.

2. Obstruct outflow of left ventricle: Aortic 2. Treat aortic valve disease, HCM
stenosis, HCM. a. More afterload = more work
b. More oxygen required
• LV compensates for increased afterload by thickening (hypertrophy) in order to decrease

wall tension.
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❖ Venous vasodilators (eg, nitrogycerin) → ↓ preload.

❖ Arterial vasodilators (eg, hydralazine) → ↓ afterload.
❖ ACE inhibitors and ARBs ↓ both preload and afterload.
Heart Rate
• Increases cardiac output under physiologic conditions.
• Mainly regulated by sympathetic nervous system.
• Also increased by sympathomimetic drugs.
• Decreased by beta blockers and calcium blockers.
• At pathologic heart rates ↑ HR = ↓ CO.
Cardiac output equations
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Work of the heart

• Myocardial oxygen demand is increased by:
1. ↑ Contractility.
2. ↑ Afterload (proportional to arterial pressure).
3. ↑ Heart Rate.
4. Diameter of ventricle (↑ wall tension).
• UW: perfusion of the heart is mainly during diastole. The systolic reduction of the coronary
flow is greatest in the subendocardial myocardium of the LV.
Cardiovascular Response to Exercise

• Process begins with muscle contraction → ATP consumed → oxygen consumed (need more
ATP) → Result: Local hypoxia in muscle tissue → Vasodilation occurs.
▪ Multiple VD mediators released into plasma:
▪ Adenosine generated from ATP consumption
▪ Lactate
▪ Carbon dioxide, potassium
▪ Vasodilatation → ↓ total peripheral resistance (TPR) → ↓ DBP.
• Sympathetic nervous system activated:
▪ Increase HR → ↑ CO (to meet the metabolic needs of the body).
▪ Results in ↑ systolic blood pressure (SBP).
▪ Venous constriction → ↑ preload → more ↑ CO.
▪ Vasoconstriction in some areas (gut, skin) → redistributes blood to important areas
(i.e. heart/muscles).
• NET result → “↑ SBP, ↓ DBP”
▪ Pulse pressure → increases.
▪ MAP → remains slightly constant (only increase 20-40).
• Fast HR → shortens diastole → LESS coronary filling time:
▪ Only way to get more oxygen is coronary vasodilation → increased blood flow.
▪ The heart cannot extract more O2 unlike other tissues.
▪ Cardiac tissue extracts maximum oxygen from RBCs.
▪ Cannot extract more to meet increased demand.
• KQB: Exercise has 2 types:
▪ Dynamic → increase blood flow d2 metabolic VD of arterioles.
▪ Static (weightlifting) → skeletal ms → compress BV → increase vascular resistance
→ decrease blood flow.
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Lusitropy
• Lusitropy = myocardial relaxation “Opposite of contractility”
• Contributes to increased preload → ↑ cardiac output.
• Increased with exercise.
• Mediated by SERCA.
▪ SERCA takes up calcium → relaxation.
▪ SERCA is regulated by a protein called phospholamban (PLB).
▪ Phospholamban is an inhibitor to SERCA.
▪ Sympathetic stimulation “beta receptors” → phosphorylates PLB → ↓ PLB → ↑
SERCA → faster relaxation → faster contraction.
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Flow Equations
• Flow “CO” = ΔP / TPR
• Flow (Q) = Velocity (V) * Area (A):
Resistance and Compliance
Total Peripheral Resistance

• Resistance to flow → more work for heart.
• What resists forward flow out of heart?
1. Types of vessels (i.e. pipes/tubes).
2. Thickness of blood (viscosity).
• Types of Vessels:
1. Arterioles = “resistance vessels” → major determinant of total peripheral resistance.
▪ Vasoconstriction = ↑ TPR, Vasodilation = ↓ TPR.
2. Veins provide most of blood storage capacity.
• Viscosity: depends mostly on hematocrit:
1. Low viscosity: Anemia.
2. High viscosity: Polycythemia, Multiple myeloma “hyperproteinemia”, Spherocytosis.
• Radius
o Changes in radius → large change in resistance.
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USMLE Endpoint
Series and Parallel Circuits
• Human organs arranged in parallel.
• Resistances add up differently in series than in parallel.
• Organ removal “eg, nephrectomy” → ↑ TPR → ↓ CO.

• UW: removal of kidney or any other organ:
-↑ TPR (as organs are arranged in parallel)
-↓ CO
-normal arterial blood pressure (MAP= CO*TPR)
-↓ total renal blood flow (there is only one kidney)
Application of flow equation

• Flow “CO” = ΔP / Resistance.
• Blood flow to the body = CO
▪ ΔP = Arterial pressure – right atrial pressure
▪ R = Total peripheral resistance (TPR) = Systemic vascular resistance (SVR)
• Blood flow to the lungs = CO
▪ ΔP = Pulmonary artery pressure – left atrial pressure
▪ R = Pulmonary vascular resistance (PVR)
• Blood flow in systemic circulation is the same in pulmonary circulation.
▪ The pulmonary circulation is low resistant, high capacitance circulation.
Velocity and Area

• Flow (Q) = CO = Velocity (V) * Area (A).
• Cardiac output moves through system (same flow).
▪ Different vessels → different area, velocity
▪ Area ↑↑, velocity ↓↓
• Capillaries have highest total cross-sectional area and lowest flow velocity.
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Flow Properties of Blood Vessels
Law of Laplace
• Wall tension or wall stress.
• Applies to vessels and cardiac chambers.
• ↑ Tension → ↑ O2 demand → ischemia/angina.
• Afterload: Increases pressure in left ventricle

▪ Hypertension, aortic stenosis → increase wall tension → “Pressure overload”.
• Preload: Increases radius of left ventricle
▪ Chronic valvular disease (aortic/mitral regurgitation) → increase wall tension →
“Volume overload”
Pressure overload Volume overload
▪ Due to increased afterload. ▪ Due to increased preload.

▪ Hypertension, aortic stenosis. ▪ Chronic valvular disease.
▪ Concentric hypertrophy to the ventricles: ▪ Eccentric hypertrophy to the ventricles:
o Sarcomeres added in parallel. o Sarcomeres added in series → Longer
o Left ventricular mass increased myocytes.
o Wall thickness increased o Left ventricular mass increased.
o Decreased compliance (stiff ventricle) o Wall thickness NOT increased.
o Often seen in diastolic heart failure
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❖ KQB: old patient with wide pulse pressure HTN, why? → Aortic stiffness, as atherosclerosis
→ ↓ compliance → ↑ pulse pressure.
❖ Aortic regurge → volume overload → synthesis of new sarcomeres in series → eccentric
hypertrophy.
❖ Aortic stenosis → pressure overload → synthesis of new sarcomeres in parallel →
concentric hypertrophy.
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Regulation of blood pressure

• Blood pressure is required for perfusion of tissues.
• Varies with sodium/water intake.
• Regulated by nervous system.
Baroreceptors
• Blood pressure sensors via stretch.
• Give signal central nervous system (brain).
• Response of the brain is via autonomic nervous system: Modify:
▪ Heart rate/contractility.
▪ Arterial tone (vasoconstriction).
▪ Venous tone (more tone = more preload to ventricle.)
▪ Renal renin release.
Aortic arch receptors Carotid sinus receptors
• Senses elevated blood pressure. • Senses low and high blood pressure.
• Poor sensing of low blood pressure. • Most important baroreceptor.
• Modifies signals over wider range of blood
pressure.
❖ Response to hypotension:
▪ ↓ Arterial pressure → ↓ stretch afferent baroreceptor firing → ↑ efferent sympathetic firing
and ↓ efferent parasympathetic stimulation → vasoconstriction, ↑ HR, ↑ contractility, ↑ BP.
▪ Important in the response to severe hemorrhage.
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USMLE Endpoint
❖ Response to hypertension:
▪ Carotid massage → ↑ pressure on carotid sinus → ↑ stretch → ↑ efferent parasympathetic
firing → ↑ AV node refractory period → ↓ HR.
▪ Component of Cushing reflex:
✓ Triad of hypertension, bradycardia, and respiratory depression.
Chemoreceptors:
• Peripheral:
▪ Carotid and aortic bodies.
▪ Stimulated by ↓ Po2 (< 60 mm Hg), ↑ Pco2, and ↓ pH of blood.
• Central:
▪ Stimulated by changes in pH and Pco2 of brain interstitial fluid, which in turn are
influenced by arterial CO2.
▪ Do not directly respond to Po2.
Coronary Blood Flow

• The coronary artery fills during diastole.
• In tachycardia, less time in diastole → less flow.
• Epicardium → site of coronary arteries.
• Subendocardium receives smallest amount blood flow.
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USMLE Endpoint
Cardiac circulation
• Three specific features distinguish cardiac circulation from blood flow to skeletal muscle and
viscera:
1. The heart is perfused only during diastole:
▪ Myocardial contraction during systole leads to compression of the coronary vessels and
disruption of blood flow.
▪ Wall tension is highest near the endocardium, making the subendocardial region the
most prone to ischemia.
2. Myocardial oxygen extraction is very high:
▪ The heart has a capillary density far exceeding that of skeletal muscle.
▪ Oxygen extraction from arterial blood is very effective within the heart as the resting
myocardium extracts 60%-75% of oxygen from blood.
▪ This amount is higher than that extracted by any other tissue or organ in the body.
▪ As a result, the cardiac venous blood in the coronary sinus, before it reaches the right
atrium and mixes with blood returning from the systemic circulation, is the most
deoxygenated blood in the body.
3. Myocardial oxygen demand and coronary blood flow are tightly coupled:
▪ Because oxygen extraction by the resting heart is already very high, there is little
capacity to increase myocardial oxygen extraction during periods of increased oxygen
demand (eg, during exercise).
▪ Therefore, increased oxygen delivery to the heart can be achieved only through
increased coronary blood flow.
▪ Adenosine and nitric oxide are the most important vasodilators responsible for
increasing coronary flow.
Nitric Oxide
• Synthesized from arginine by nitric oxide synthase.
▪ As a precursor of nitric oxide; arginine supplementation may play an adjunct role in the
treatment of conditions that improve with vasodilation such as stable angina.
• Synthesized by endothelial cells and causes vascular smooth muscle relaxation by a
guanylate cyclase-mediated cGMP second messenger system.
• Nitric oxide Vs. adenosine:
▪ NO → VD on large and pre-arteriolar vessels.
▪ Adenosine → VD on small arterioles.
• NB: Nervous input has very little role on coronary blood flow.
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Autoregulation
• It is the mechanism by which blood flow to each organ remains constant over a wide range of
perfusion pressures.
Pressure-volume Loop & cardiac cycle:
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UW: ↑ESV→ more volume remaining in the ventricle after contraction.
Pressure-Volume Loop Alterations:
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• UW: Na nitroprusside: balanced dilator → venodilator (↓preload) & arteriodilator (↓afterload) →

so, SV remain constant.
• UW: furosemide (diuresis) ↓ preload → ↓ EDV.
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• Spinal anesthesia:
▪ ↓ Venous tone → ↓ venous return → ↓ preload.
▪ Has no rule with TPR.
• UW: AV shunt → blood shunts from arterioles (↓afterload) to veins (↑preload).
• UW: Chronic anemia:

▪ ↑ CO → this causes an increase in the slope and height of the cardiac output graph.
▪ ↑ VR due to decreased blood viscosity.
• Rx: ↓Afterload → ↑ SV → ↑ width of the curve.
• Rx: post-radiation therapy → constrictive pericarditis → ↓ EDV.
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LV pressure curve:
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Starling curve
• Force of contraction is proportional to end-diastolic length of cardiac muscle fiber (preload).
▪ Contractility is increased with catecholamines, positive inotropes.
▪ Contractility is decreased with loss of myocardium (e.g., MI), BB (acutely), non-dihydropyridine
CCBs, dilated cardiomyopathy.
• UW: patient with shock then infused 2L saline → ↑ preload → ↑ end diastolic sarcomere
length.
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Cardiac and vascular function curves:
• Mean Systemic Filling Pressure (MSFP) → Pressure if heart stops.

• UW: which ↑CO & ↑VR with the same MSFP? → ↓TPR (exercise & acute AV shunt)
Which ↑CO & ↑VR with ↑MSFP? → Chronic AV fistula d2 sympathetic and renal
compensation → ↑contractility, ↑vascular tone and ↑blood volume.
Exercise on cardiac and vascular function curves:

• ↑CO & ↑VR & ↓TPR.
• MSFP is constant as MSFP = CO × TPR. (↑CO & ↓TPR)
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Wigger’s diagram
• UW: dicrotic notch → represents the elasticity of the aorta; lost in AR, Marfan and
syphilis.
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Aortic stenosis
• UW: In aortic stenosis curve: which point corresponds to the maximum point of murmur?
Answer → B. normally, pressure in aorta = pressure in LV during systole.
Mitral stenosis
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Mitral regurgitation
• V-wave:
▪ LA pressure d2 passive filling during systole.
▪ An abnormally prominent, upsloping left atrial “V wave” during cardiac
catheterization is a major hemodynamic finding of mitral regurge.
Aortic regurgitation
• UW: How to diagnose AR on aortic pressure curve?

1- Absence of diacritic notch.
2- Steep diastolic decline on the curve.
3- High peak of aortic pressure + wide pulse pressure.
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Jugular venous pressure curve:

• Indirectly measures the pressure in the right atrium.
➢ ↑ RAP → ↑JVP: Causes:
▪ Heart failure, fluid overload.
▪ Constrictive pericarditis, cardiac tamponade.
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• A wave—atrial contraction.
▪ Absent in atrial fibrillation (no organized atrial contraction).
▪ Cannon a wave in AV dissociation “complete heart block” → (atria against closed
tricuspid valve).
• C wave—RV contraction (closed tricuspid valve bulging into atrium).
• X descent:
▪ Atrial relaxation and downward displacement of closed tricuspid valve during
ventricular contraction.
▪ Absent in tricuspid regurgitation.
• V wave:
▪ ↑RT atrial pressure due to filling (“villing”) against closed tricuspid valve.
▪ Giant v wave in Tricuspid regurgitation.
• Y descent:
▪ RA emptying into RV.
▪ Rapid deep descent in y-descent → in constrictive pericarditis.
LA pressure curve:
• UW: pt with MS (↑LA pressure on the curve) where is the site of the opening snap?
Answer: C → OS is early diastolic shortly after the aortic component of the second heart sound.
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Heart sounds:
• S1: mitral and tricuspid valve closure. Loudest at mitral area.
• S2: aortic and pulmonary valve closure. Loudest at left upper sternal border.
• S3: in early diastole during rapid ventricular filling phase.
▪ Due to rushing of blood into a partially filled ventricle or very stiff ventricle.
▪ Best heard with:
✓ Bell of the stethoscope pressed lightly over the apex (the bell detects low frequency
voices)
✓ Left lateral decubitus.
✓ At the end of expiration.
• S4:
▪ In late diastole (“atrial kick”).
▪ Left atrium must push against stiff LV wall.
▪ High atrial pressure.
▪ Best heard at apex with patient in left lateral decubitus position.
▪ Associated with ventricular hypertrophy.
• Rx: in aortic stenosis ↑ isovolumetric contraction phase d2 need to ↑ pressure to open the
stenotic valve.
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Splitting
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Auscultation of the heart
• UW: Left lateral decubitus ↑ intensity of which murmurs? → MS, MR, left sided S3 & S4
• NB: Inspiration → ↑ tricuspid murmurs.
Expiration → ↑ mitral murmurs.
• KQB: Inspiration → ↑ -ve intrathoracic pressure → ↑ venous return → ↑ blood in RV →
pooling of blood of blood in lungs → *↓ systolic arterial pressure.
▪ ↑ HR.
▪ ↓ LV EDP & ↑ RV EDP.
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Valsalva Maneuver
• Bear down as if moving bowels.
• Phase I (few seconds):
➢ ↑ thoracic pressure
➢ ↓ venous return (compression of veins → ↑RA pressure)
➢ Transient rise in aortic pressure (compression)
➢ ↓ heart rate and AV node conduction (baroreceptors)
• Phase II
➢ ↓ Preload → ↓ cardiac output.
➢ ↑ Heart rate and AV node conduction (baroreceptors).
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Heart murmurs:
• Systolic → AS & MR/TR & MVP VSD.
• Diastolic → AR & MS.
• Continuous → PDA.
Systolic murmurs
Aortic stenosis
• Crescendo-decrescendo systolic ejection murmur and soft S2 (ejection click may be
present). Loudest at heart base; radiates to carotids.
• LV >> aortic pressure during systole.

• “Pulsus parvus et tardus”—pulses are weak with a delayed peak.
• Can lead to Syncope, Angina, and Dyspnea on exertion (SAD).
• Most commonly due to age related calcification in older patients (> 60 years old) or in
younger patients with early-onset calcification of bicuspid aortic valve.
• Severe Disease Findings:
➢ Late‐peaking murmur: Slow flow across stenotic valve.
➢ Soft/quiet S2: Stiff valve can’t slam shut.
➢ Pulsus parvus et tardus:
▪ Weak and small carotid pulses
▪ Delayed carotid upstroke
• UW: Aortic stenosis early can cause diastolic dysfunction and hypertrophy then late can
cause systolic dysfunction and LVF.
• UW: patient with AS then developed AF → sudden onset of acute HF (pulmonary edema &
hypotension):
▪ Cause: sudden loss of LV preload.
▪ Explanation: acute AF most likely
precipitated sudden HF in chronic AS as
AF → loss of atrial systolic kick → ↓LV
preload → ↓LVEDV → ↓CO with AS
that caused concentric LV hypertrophy
which worsen the case.
• UW: holosystolic murmurs → MR & TR &
VSD.
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Mitral/tricuspid regurgitation
• Holosystolic, high-pitched “blowing murmur.”
• Mitral: loudest at apex and radiates toward axilla. MR is often due to ischemic heart
disease (post-MI), MVP, LV dilatation.
• Tricuspid: loudest at tricuspid area. TR commonly caused by RV dilatation.
• Rheumatic fever and infective endocarditis can cause either MR or TR.
• In MR, what is the best indicator for severity of the problem?
➢ The presence of audible S3 NOT the holosystolic murmur intensity as the later doesn’t
correlate well with the regurgitant volume but correlate with the effective regurgitant orifice.
NOT S4 as MR+S4 → end stage decompensation of severe MR → LV failure; however,
many patients with severe MR may not have developed LV failure.
• Case: HTN + S3 + holosystolic murmur over the apex but the murmur and the S3
disappeared after diuretics and vasodilators → Dx: Functional MR which caused by either:
➢ Transient hemodynamic factor causing LV dilatation → “Acute LV dilatation can separate
otherwise normal mitral valve”.
➢ OR papillary ms ischemia.
• Forward-to-regurgitant flow ratio:
➢ “In MR, some blood is pumped forward through the aortic valve (forward stroke volume),
while some blood is forced backwards through incompetent valve (regurgitant SV).
➢ Determines left ventricular afterload in patients with mitral regurgitation.
➢ Decreasing afterload will increase forward flow while reducing regurgitant flow.
➢ An increase in left ventricular end diastolic volume can contribute to or worsen mitral
regurgitation when the degree of regurgitation is dependent on left ventncular size (eg, in
dilated cardiomyopathy).
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Mitral valve prolapse
• Late systolic crescendo murmur with midsystolic click (MC; due to sudden tensing
of chordae tendineae).
• Most frequent valvular lesion.
• Best heard over apex.
• Loudest just before S2. Usually benign.
• Can predispose to infective endocarditis.
• Can be caused by myxomatous degeneration (1° or 2° to connective tissue disease such as
Marfan or Ehlers-Danlos syndrome), rheumatic fever, chordae rupture.
Ventricular septal defect

• Holosystolic, harsh-sounding murmur. Loudest at tricuspid area.
Diastolic murmurs
Aortic regurgitation (AR)
• High-pitched “blowing” early diastolic decrescendo murmur.
• Long diastolic murmur, hyperdynamic pulse, and head bobbing when severe and chronic.
• Wide pulse pressure.
• Often due to aortic root dilation, bicuspid aortic valve, endocarditis, rheumatic fever.
• Progresses to left HF.
• Murmur best heard when patient sits up and leans forward? → AR.
• UW: In AR, what maintains CO??
▪ ↑ LV preload
▪ Eccentric LVH
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Mitral stenosis
• Delayed rumbling mid-to-late diastolic murmur.
• Follows opening snap (OS; due to abrupt halt in leaflet motion in diastole, after rapid
opening due to fusion at leaflet tips).
• ↓ Interval between S2 and OS correlates with ↑ severity: Higher left atrial pressure → ↓
time to opening snap.
• LA >> LV pressure during diastole.
• Often a late (and highly specific) sequela of rheumatic fever.
• Chronic MS can result in LA dilatation → dysphagia/hoarseness via compression of
esophagus/left recurrent laryngeal nerve, respectively.
• UW: in MS the opening snap is best heard at mitral opening in pressure volume curve.
• UW: The best indicator of MS severity → A2 – OS interval → the shorter the interval the
more severe the stenosis.
▪ NOT the rumble → as it depends on the patient anatomy.
▪ NOT the presystolic accentuation → as it indicates LA contraction.
• UW: How to differentiate between OS of MS & splitting of S2?
▪ Splitting → ↑ with inspiration.
▪ OS → ↑ with expiration
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• UW: in MS → normal LV diastolic pressure. But if MS + ↑ LVEDP → suspect presence of

additional lesion e.g
1. Rheumatic involvement of aortic valve (typically cause combined AR & AS)
2. Infective endocarditis superimposed aortic valve deformity.
• MS + stroke → d2 LA dilatation → atrial mural thrombus.
• MS + TR → d2 ↑ LA pressure → ↑ PCWP → pulmonary HTN → pulmonary vascular
sclerosis → ↓ compliance → RV dilatation → functional TR.
• UW: Late diastolic murmur eliminated by atrial fibrillation → MS & TS.
Continuous murmurs
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Myocardial action potential

• Also occurs in bundle of His and Purkinje fibers.
• Phase 0:
▪ Rapid upstroke and depolarization.
▪ Voltage-gated Na+ channels open.
• Phase 1:
▪ Initial repolarization.
▪ Voltage-gated K+ channels begin to open.
• Phase 2:
▪ Plateau → Ca2+ influx through voltage-gated Ca2+ channels balances K+ efflux.
▪ Ca2+ influx triggers Ca2+ release from sarcoplasmic reticulum and myocyte contraction.
▪ ↓ With CCBs & ↑ with K channel antagonists.
• Phase 3:
▪ Rapid repolarization.
▪ Massive K+ efflux due to opening of voltage-gated slow K+ channels and closure of
voltage-gated Ca2+ channels.
▪ Execution by K infusion → ↑ K in ECF → no K efflux → no repolarization → arrest.
• Phase 4:
▪ Resting potential.
▪ High K+ permeability through K+ channels → constant outward leak of K+.
▪ Na+ and Ca2+ channels are closed.
▪ UW: the resting potential of cardiac ms (phase 4) is -90 not -70, why? → to reduce the
risk for arrhythmia, as larger stimulus is needed to excite the cells.
• In contrast to skeletal muscle:
▪ Cardiac muscle action potential has a plateau, which is due to Ca2+ influx and K+ efflux.
▪ Cardiac muscle contraction requires Ca2+ influx from ECF to induce Ca2+ release from
sarcoplasmic reticulum (Ca2+-induced Ca2+ release).
▪ Cardiac myocytes are electrically coupled to each other by gap junctions.
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Cardiac muscle contraction
• UW: Verapamil is a CCB but doesn’t affect skeletal ms?

▪ Skeletal muscles:
o Doesn’t depend on extracellular calcium → doesn’t require extracellular
calcium influx for excitation contraction coupling.
o Ca comes from SR not from outside.
▪ Cardiac and smooth muscles:
o Depends on extracellular calcium entering by voltage gated L-type calcium
channels for excitation contraction coupling.
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Pacemaker action potential

• Occurs in the SA and AV nodes.
• Key differences from the ventricular action potential include:
1. Phase 0 = upstroke:
▪ Opening of voltage-gated Ca2+ channels.
▪ Fast voltage-gated Na+ channels are permanently inactivated because of the less
negative resting potential of these cells.
▪ Results in a slow conduction velocity that is used by the AV node to prolong
transmission from the atria to ventricles.
2. Phases 1 and 2 are absent.
3. Phase 3 = repolarization:
▪ Inactivation of the Ca2+ channels and ↑ activation of K+ channels → ↑
K+ efflux.
4. Phase 4 (slow spontaneous diastolic depolarization)
▪ Occurs due to:
• Closure of repolarizing K channels.
• Slow influx of Na through funny channels.
• Opening of T-type Ca channels
▪ If channels
• Responsible for a slow, mixed Na+/K+ inward current.
• Different from INa in phase 0 of ventricular action potential.
• Accounts for automaticity of SA and AV nodes.
▪ The slope of phase 4 in the SA node determines HR.
▪ ACh/adenosine ↓ the rate of diastolic depolarization and ↓ HR, while
catecholamines ↑ depolarization and ↑ HR.
▪ Sympathetic stimulation ↑ the chance that If channels are open and thus ↑ HR.
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• Threshold potential:
▪ The amount of depolarization required to initiate the action potential.
▪ Increased by class 1 antiarrhythmic (Na channel blockers) and class 4 (CCBs).
• Role of Verapamil in pacemaker action potential:
▪ Slows diastolic depolarization by ↓ Ca influx during phase 0 and the later part of
phase 4 → ↓ rate of SA node firing and slows AV node conduction.
• Role of Adenosine and acetylcholine in action potential:
▪ Pacemaker cells:
✓ Affect phase 4 of the action potential reducing the rate of spontaneous
depolarization in cardiac pacemaker cells.
✓ Inhibits L-type Ca channels → further prolonging the depolarization time.
✓ These actions result in a transient slowing of the sinus rate and an increase
in AV nodal conduction delay.
✓ Adenosine is useful in the termination of paroxysmal supraventricular
tachycardia.
▪ Myocytes:
✓ Activates potassium channels →↑ K conductance → membrane potential
remains negative for a longer period.
▪ Acetylcholine behaves similarly by increasing outward K. conductance while
decreasing inward Ca and Na currents during phase 4.
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• Norepinephrine & sympathetic on pacemaker action potential:
▪ Opens L-type Ca channel and Na channels in phase 4 → ↓ time taken to reach the
threshold → ↑ automaticity.
• Ivabradine:
▪ Drug that ↓HR without affecting contractility.
✓ As it acts only on phase 4 of the SA node unlike other drugs decreasing HR.
✓ Ivabradine selectively inhibits the funny sodium channels prolonging the slow
depolarization phase (phase 4) and slowing the sinoatrial node firing rate.
▪ It has a negative chronotropic effect with no effect on cardiac contractility
(inotropy) and/or relaxation (lusitropy).
▪ Used in chronic HF with ↓EF and persistent symptoms despite approprtiate ttt.
↓risk of hospitilization d2 HF.
• Inotropic → ↑ contractility → by ↑ inward Ca current.

• Chronotropic → ↑ HR → by ↑ inward Na current→ ↑ SA node firing.
• Dromotropic → ↑ conduction velocity through AV node → by ↑ inward Ca current.
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Pacemakers
• SA node
▪ Dominant pacemaker of the heart.
▪ Located at junction of RA and SVC.
▪ Beats at 60-100 bpm.
• Other pacemakers exist but are slower: If SA node fails, others takeover
▪ AV node (40-60 bpm):
✓ Located in posteroinferior part of interatrial septum.
✓ Blood supply usually from RCA.
✓ 100-msec delay allows time for ventricular filling.
▪ HIS (25-40 bpm)
▪ Bundle branches (25-40 bpm)
▪ Purkinje fibers (25–40 bpm)
Conduction Velocities:
▪ SLOWEST conduction is through AV node.
▪ Very important so ventricle has time to fill.
▪ Purkinje fibers → fastest conduction.
▪ Purkinje > Atria > Vent > AV node.
• Conduction pathway:
▪ SA node → atria → AV node → bundle of His → right
and left bundle branches → Purkinje fibers →
ventricles; left bundle branch divides into left anterior
and posterior fascicles.
• Determining Heart Rate
▪ 3 – 5 big boxes between QRS complex.
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Electrocardiogram
ECG waves
• P wave:
▪ Atrial depolarization. Atrial repolarization is masked by QRS complex.
▪ No p waves:
✓ Irregular rhythm → Atrial fibrillation – irregularly irregular.
✓ Regular rhythm → Hidden p waves: retrograde, Supraventricular tachycardias (SVTs),
Ventricular tachycardia.
▪ P waves present, irregular rhythm:
✓ Sinus rhythm with PACs
✓ Multifocal atrial tachycardia
✓ Sinus with AV block
• PR interval:
▪ Time from start of atrial depolarization to start of ventricular depolarization.
▪ It reflects conduction through the AV node.
▪ Normally < 200 msec.
✓ If > 200 msec. → first degree heart block is said to be present
• QRS complex:
▪ Ventricular depolarization → phase 0 in ventricular contraction (in myocardial action potential
curve).
▪ Normally < 120 msec. Wide QRS > 120 msec → bundle branch block or ventricular tachycardia.
• QT interval:
▪ It represents the time taken for ventricular depolarization and repolarization, effectively the
period of ventricular systole from ventricular isovolumetric contraction to isovolumetric
relaxation (mechanical contraction of the ventricles).
▪ Short Qt: Hypercalcemia.
▪ Prolonged Qt: Hypocalcemia, drugs, LQTS
• T wave:
▪ Ventricular repolarization. T-wave inversion may indicate ischemia or recent MI.
▪ Peaked T waves: ↑ K, Early ischemia (hyperacute).
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• J point:
▪ Junction between end of QRS complex and start of ST segment.
• ST segment:
▪ Isoelectric, ventricles depolarized.
• U wave:
▪ Prominent in hypokalemia (think hyp“U”kalemia), bradycardia.
QRS Axis
• The axis of the heart tends to move

▪ Toward the hypertrophied tissue and
▪ Away from the infarcted tissue
• Rt Axis Deviation → RVH, MI on the Lt and conduction deficit on the Rt.
• Lt Axis Deviation → LVH, MI on the RT and conduction deficit on the Lt.
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Axis Quick Method
• First, glance at aVr → it should be negative.
• If upright, suspect limb lead reversal.
Torsades de pointes
• Torsades de pointes = twisting of the points.
• Polymorphic ventricular tachycardia characterized by shifting sinusoidal waveforms on ECG.
• Can progress to ventricular fibrillation (VF).
• Long QT interval predisposes to torsades de pointes.
• Caused by drugs, ↓ K+, ↓ Mg2+, ↓ Ca+2, congenital abnormalities.
• Treatment includes magnesium sulfate.
Congenital long QT syndrome

• Inherited disorder of myocardial repolarization, typically due to ion channel defects
➢ ↑ Risk of sudden cardiac death due to torsades de pointes.
• Includes:
➢ Romano-Ward syndrome:
▪ Autosomal dominant, pure cardiac phenotype (no deafness).
➢ Jervell and Lange-Nielsen syndrome:
▪ Autosomal recessive, sensorineural deafness.
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Brugada syndrome
• Autosomal dominant disorder most common in Asian males.
• Mutations in the cardiac sodium channel SCN genes.
• ECG pattern of pseudo-right bundle branch block and ST elevations in V1-V3.
• ↑ Risk of ventricular tachyarrhythmias and SCD.
• Prevent SCD with implantable cardioverter-defibrillator (ICD).
• Patients with schizophrenia appear significantly more likely to have Brugada.
Wolff-Parkinson-White syndrome
• Most common type of ventricular preexcitation syndrome.
▪ Abnormal heart rhythm in which the ventricles of the heart become depolarized too early,
which leads to their partial premature contraction
• Abnormal fast accessory conduction pathway from atria to ventricle (bundle of Kent)
bypasses the rate-slowing AV node → ventricles begin to partially depolarize earlier →
characteristic delta wave with widened QRS complex and shortened PR interval on ECG.
• May result in reentry circuit → supraventricular tachycardia.
▪ Recurrent temporary arrhythmia in otherwise normal person → WPW syndrome.
• Don’t slow AV node with (digoxin, CCBs, BBs or adenosine) but block the accessory
pathway with (antiarrhythmic Ia & III).
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Atrial fibrillation
• Chaotic and erratic baseline with no discrete P waves in between irregularly QRS complexes.
• Irregularly irregular heartbeat.
• Risk factors:
✓ Most common risk factors include hypertension and coronary artery disease (CAD).
✓ Occasionally seen after binge drinking ("holiday heart syndrome")
• Can lead to thromboembolic events, particularly stroke.
• Treatment includes anticoagulation, rate control, rhythm control, and/or cardioversion.
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UW: In AF, which factor determines the ventricular rate?

➢ AV node refractory period.
“ AF occurs due to irregular electrical activity in the atrium; while some of the atrial
impulses are transmitted to the ventricles, most are not due to AV nodal refractory period”
Atrial flutter
• A rapid succession of identical, back-to-back atrial depolarization waves.
• The identical appearance accounts for the "sawtooth" appearance of the flutter waves.
• Treat like atrial fibrillation. Definitive treatment is catheter ablation.
Ventricular fibrillation
• A completely erratic rhythm with no identifiable waves.
• Fatal arrhythmia without immediate CPR and defibrillation.
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AV block
First-degree AV block
• The PR interval is prolonged (> 200 msec).
• Benign and asymptomatic. No treatment required.
Second-degree AV block
1. Mobitz type I (Wenckebach):
a. Progressive lengthening of PR interval until a beat is “dropped” (a P-wave not followed by
a QRS complex).
b. The level of block is usually the AV node.
c. Usually asymptomatic. Variable RR interval with a pattern (regularly irregular).
2. Mobitz type II
a. Dropped beats that are not preceded by a change in the length of the PR interval (as in type I).
b. Due to defect in His-Purkinje system. For this reason, the PR interval is constant as the AV
node is normal.
c. May progress to 3rd-degree block. Often treated with pacemaker.
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Third-degree (complete) AV block

➢ Conduction between the SA and AV nodes is impaired → AV nodal cells become
pacemakers → SA node impulses cause atrial contraction while impulses generated
by the AV node cause ventricular contraction.
➢ The ventricular pacing is coming from AV node which becomes the pacemaker.
• ECG:
➢ AV dissociation: the atria and ventricles depolarize independently of each other →
P waves and QRS complexes not rhythmically associated
➢ QRS complexes are narrow since ventricular depolarization proceeds normally.
➢ The AV node produces a heart rate of 45-55 beats per minute.
• Usually treated with pacemaker.
• Can be caused by Lyme disease.
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Bundle branches block

• Both bundle branches blocked → results in AV block; form of HIS-Purkinje system disease.
• ONE bundle branch blocked:
➢ Does not cause AV block
➢ Normal PR interval
➢ QRS will be prolonged
• Symptoms: None
➢ Identified incidentally on ECG
• May progress to AV block (need for pacemaker)
➢ Interfere with detection of ischemia
➢ ST elevations, T-wave inversions can be normal.
• Causes:
➢ Often caused by slowly progressive fibrosis/sclerosis
➢ More common in older patients
➢ Can result from “structural heart disease”
➢ LBBB: Prior MI, cardiomyopathy
➢ RBBB: Right heart failure
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Right Bundle Branch Block
Left bundle branch block
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Atrial natriuretic peptide & brain natriuretic peptide

Atrial natriuretic peptide
• Released from atrial myocytes in response to → blood volume and atrial pressure.
• Acts via cGMP.
• Mechanism of action:
1. Kidney:
▪ Dilate afferent and constricts efferent, ↓ Na reabsorption, ↓ renin → diuresis.
▪ Contributing to “aldosterone escape” mechanism.
2. Adrenal gland → ↓ aldosterone.
3. Blood vessels → VD, ↑ capillary permeability.
B-type (brain) natriuretic peptide

• Released from ventricular myocytes in response to ↑ tension.
• Similar physiologic action to ANP, with longer half-life.
• BNP blood test used for diagnosing HF (very good negative predictive value).
• Available in recombinant form (nesiritide) for treatment of HF.
• UW: Neprilysin
▪ Cleaves and inactivates endogenous peptides including natriuretic peptides (eg.
BNP), glucagon, oxytocin and bradykinin.
▪ Inhibition of neprilysin e.g., sacubitril leads to increased levels of endogenous
natriuretic peptides, which promote beneficial effects in heart failure.
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Normal cardiac pressures

• Right-sided pressures in the heart are lower than left-sided pressures due to lower resistance
in the pulmonary vasculature.
• Pulmonary capillary wedge pressure (PCWP)
▪ Good approximation of the left atrial pressure.
▪ PCWP= LA EDP = LV EDP
▪ In mitral stenosis, PCWP > LV EDP.
▪ PCWP is measured by Swan-Ganz catheter.
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Exercise physiology
Capillary fluid exchange
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• UW: Venous thrombosis is causing edema just like CHF → causes edema by ↑ capillary
hydrostatic pressure.
• UW: patient e CHF and ↑ CVP but there is no edema! Why? → D2 ↑ tissue lymphatic drainage
which can compensate for moderate CVP elevation to prevent development of clinically apparent
edema.
3rd Spacing
• Intracellular fluid – 1st space → About 2/3 body fluid.
• Extracellular fluid – 2nd space → About 1/3 body fluid.
• Third spacing - fluid where it should NOT be:
✓ Pleural effusions, Ascites, Cerebral edema.
• Low intravascular volume/High total volume
• Occurs post-op, sepsis.
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CVS PATHOLOGY
Hypertension
• Defined as persistent systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg.
PRIMARY HTN:
• HTN of unknown etiology (90% of cases). Related to ↑ CO or ↑ TPR.
• Risk factors: Age, obesity, diabetes, physical inactivity, excess salt intake, excess alcohol
intake, cigarette smoking, family history; African American > Caucasian > Asian.
Secondary HTN:
• HTN due to an identifiable etiology (10% of cases).
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Renal artery stenosis
Fibromuscular dysplasia
• Physical examination:
• Hum or bruit in costovertebral angle due to well-developed
collaterals.
• Right renal is more affected than left → renin and angiotensin
↑ (2° hyperaldosteronism).
• Carotid bruit can also be heard
• Angiography: “string of beads” pattern to renal artery.
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Hypertensive crisis
Hypertension complications:
• CAD, LVH, HF, atrial fibrillation; aortic dissection, aortic aneurysm; stroke; chronic kidney
disease (hypertensive nephropathy); retinopathy.
Hyperlipidemia signs
• Xanthomas:
▪ Plaques or nodules composed of lipid-laden histiocytes in skin A, especially the eyelids
(xanthelasma B).
▪ Lipid laden histiocytes: dermal accumulation of macrophages containing cholesterol
and triglycerides.
• Tendinous xanthoma:
▪ Lipid deposit in tendon C, especially Achilles.
• Corneal arcus:
▪ Lipid deposit in cornea.
▪ Common in elderly (arcus senilis D), but appears earlier in life with hypercholesterolemia
• Familial hypercholesterolemia:
▪ One of the most common autosomal dominant disorders.
▪ Cause: mutation in the LDL receptor gene in the liver which clears 70% of the LDL in
the blood → accelerated atherosclerosis → early onset coronary artery disease.
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Arterioscelorosis
• Literally, "hard arteries;" due to thickening of the blood vessel wall.
• Three pathologic patterns:- atherosclerosis, arteriolosclerosis, and Monckeberg medial calcific
sclerosis.
1- ARTERIOLOSCLEROSIS
• Narrowing of small arterioles; divided into hyaline and hyperplastic types.
Hyaline arteriolosclerosis
• Caused by proteins leaking into the vessel wall, producing vascular thickening; proteins are seen
as pink hyaline on microscopy.
• Consequence of long-standing benign hypertension or diabetes.
• Results in reduced vessel caliber with end-organ ischemia; classically produces glomerular
scarring (arteriolonephrosclerosis) that slowly progresses to chronic renal failure.
Hyperplastic arteriolosclerosis
• Involves thickening of vessel wall by hyperplasia of smooth muscle ('onion-skin' appearance).
• Consequence of malignant hypertension.
• Results in reduced vessel caliber with end-organ ischemia.
• May lead to fibrinoid necrosis of the vessel wall with hemorrhage; classically causes acute
renal failure with a characteristic 'flea-bitten' appearance.
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2- MONCKEBERG MEDIAL CALCIFIC SCLEROSIS

• Calcification of the media of muscular (medium-sized) arteries; nonobstructive.
• Not clinically significant; seen as an incidental finding on x-ray or mammography.
3- Atherosclerosis
• Plaque accumulation in arterial walls.
• Chronic inflammatory process; involves macrophages, T-cells.
• Form of arteriolosclerosis caused by accumulation of lipoproteins especially LDL.
• Underlying cause of many diseases: • Myocardial infarction • Stroke • Peripheral vascular disease
• Affected arteries:
➢ Large elastic arteries: Aorta, carotid arteries, iliac arteries.
➢ Medium‐sized muscular arteries: Coronary, popliteal
(Abdominal aorta > coronary artery > popliteal > carotid artery.)
• Risk factors:
➢ Modifiable: smoking, hypertension, hyperlipidemia (↑LDL), diabetes.
➢ Nonmodifiable: age, sex (more in men and postmenopausal women), family history.
➢ Endothelial injury or dysfunction:
▪ Details incompletely understood; believed to be related to risk factors.
▪ Cigarette smoke, high blood pressure, high cholesterol.
▪ Common sites for plaques are branch points and vessel origins (ostia).
➢ Lipids:
▪ LDL accumulation in intima → Oxidized by free radicals.
▪ Oxidized LDL scavenged by macrophages → Cannot be degraded.
▪ Macrophages become foam cells → fatty streaks.
➢ Chronic inflammation:
▪ LDL oxidized from free radicals damages endothelium, smooth muscle.
▪ Macrophages release cytokines → smooth muscle migration.
➢ Smooth muscle cells:
▪ Proliferate in intima → lay down extracellular matrix → fibrous plaques.
▪ Key growth factor: Platelet-derived growth factor “PDFG”.
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• Atheroma Growth:
➢ Fatty streaks:
▪ Macrophages filled with lipids.
▪ Form line (steak) along vessel lumen → Do not impair blood flow.
▪ Can be seen in children, adolescents.
▪ Not all progress.
➢ Atherosclerotic plaques
▪ Intima thickens, lipids accumulate.
▪ Usually patchy along vessel wall; rarely involve entire vessel wall.
▪ Usually eccentric.
UW: Vascular smooth muscle cells are the only cells within the atherosclerotic plaque capable of
synthesizing structurally important collagen and other matrix components. Progressive enlargement
of the plaque results in remodeling of the extracellular matrix and VSMC death, promoting
development of vulnerable plaques with an increased propensity for rupture.
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Atherosclerosis Complications
• Ischemia.
• Plaque rupture:
➢ Exposes thrombogenic substance → clot formation.
➢ May cause acute vessel closure (STEMI)
➢ Thrombus may embolize (stroke from carotid plaque)
• Hemorrhage into plaque:
➢ Lesions in intima causes proliferating small vessels (“neovascularization”)
➢ Contained rupture may suddenly expand lesion.
• Aneurysm:
➢ Lesions may damage underlying media.
➢ Plaque associated with abdominal aortic aneurysms.
• Dystrophic Calcification
➢ Commonly seen in atheroma.
➢ Result of chronic inflammation.
➢ Basis for “coronary CT scans”
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UW: Case Scenario: 12y + flat yellow spots on the inner surface of the aorta.
❖ Fatty streaks:
▪ Not raised, don’t disturb blood flow and shows intracellular lipid accumulation.
▪ Presents in all aortas of all children > 10 years → normal finding.
UW: Which cell does provide the major proliferative stimuli for cellular component of the
atherosclerotic plaques?
❖ PLATELETS:
▪ Endothelial injury → platelet adhesion.
▪ PDGF→ smooth ms migration from media to intima and proliferation.
▪ TGF→ interstitial collagen production.
UW: Vascular reaction to intimal injury → intimal hyperplasia and fibrosis → mediated by
smooth ms cells that migrate from the media to the intima.
▪ Fibrous plaque = intimal plaque = necrotic lipid core + fibromuscular cap.
UW: Prostacyclin (Prostaglandin I2)
▪ Synthesized by prostacyclin synthase in the capillary endothelium.
▪ Function:
1. Inhibits platelet aggregation and adhesion
2. Vasodilates and increases vascular permeability and stimulates leukocyte
chemotaxis.
▪ Normally, prostacyclin exists in dynamic balance with thromboxane A2 (TXA2), a
prostaglandin that enhances platelet aggregation and causes vasoconstriction.
▪ Prostacyclin and TXA2 together maintain capillary patency and normal blood flow.
▪ Damaged endothelial cells lose the ability to synthesize prostacyclin, and therefore
predispose to the development of thrombi and hemostasis. Synthetic prostacyclin is
used in the treatment of pulmonary hypertension peripheral vascular disease and
Raynaud syndrome.
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Aortic aneurism
• Localized pathologic dilatation of the aorta.
THORACIC ANEURYSM
• Due to weakness in the aortic wall.
• Risk factors include:
1. Hypertension.
2. Connective tissue disease (eg, Marfan syndrome) due to cystic medial degeneration:
Myxomatous changes in the media of the arteries.
3. Bicuspid aortic valve
4. 3° syphilis (obliterative endarteritis of the vasa vasorum)
▪ Results in a 'tree-bark' appearance of the aorta.
• Major complications:
1. Dilation of the aortic valve root, resulting in aortic valve insufficiency
2. Compression of mediastinal structures (e.g., airway or esophagus)
3. Thrombosis/embolism.
ABDOMINAL AORTIC ANEURYSM

• Usually arises below the renal arteries, but above the aortic bifurcation.
• Primarily due to atherosclerosis; classically seen in male smokers> 60 years old with HTN.
1. Atherosclerosis increases the diffusion barrier to the media, resulting in atrophy and
weakness of the vessel wall.
• Presents as a pulsatile abdominal mass that grows with time.
• Major complication is rupture, especially when > 5 cm in diameter; presents with triad of
hypotension, pulsatile abdominal mass, and flank pain.
1. Other complications include compression of local structures (e.g., ureter) and
thrombosis/embolism.
UW: Direct cause of AAA → transmural inflammation of the aortic wall.

Although atherosclerotic changes are frequently present in patients with AAA, these are limited
to the inner aortic wall layers. In contrast, AAAs are characterized by transmural inflammation of
the aortic wall. Chronic inflammation leads to degradation of elastin and collagen by proteases,
resulting in loss of elastin and smooth muscle cells and abnormal collagen remodeling and cross-
linking. These changes lead to weakening and progressive expansion of the aortic wall resulting
in aneurysm formation.
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USMLE Endpoint
Aortic dissection
• Longitudinal intimal tear forming a false lumen.
• Occurs in the proximal 10 cm of the aorta (high stress region) with preexisting weakness of the
media.
• Most common cause is hypertension (older adults); also associated with inherited defects of
connective tissue (younger individuals)
1. Hypertension
▪ Single most important risk factor.
▪ Results in hyaline arteriosclerosis of the vasa vasorum; decreased flow causes
atrophy of the media.
2. Marfan syndrome and Ehlers-Danlos syndrome classically lead to weakness of
the connective tissue in the media (cystic medial necrosis).
• Presents as sharp, tearing chest pain that radiates to the back +/- markedly unequal BP in
arms. CXR → mediastinal widening.
• Complications include pericardial tamponade (most common cause of death), rupture with fatal
hemorrhage, and obstruction of branching arteries (e.g., coronary or renal) with resultant end-
organ ischemia.
Stanford classification of aortic dissection

• Stanford type A refers to aortic dissections that involve any part of the ascending aorta.
▪ Usually originate in the sinotubular junction.
▪ The areas are thought to be predominantly affected due to increases in the rate of rise
of pressure and in shearing forces at these sites in patients with severe hypertension.
• Stanford type B refers to all other dissections involving the descending aorta.
▪ Typically originate close to the origin of the left subclavian artery.
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USMLE Endpoint
Cardiac ischemia
• The likelihood of MI is increased with the action of metalloproteinase → degrade collagen

→ ↓ plaque stability → plaque rupture.
Stable Angina
• Angina: Chest pain due to ischemic myocardium secondary to coronary artery narrowing or
spasm; no myocyte necrosis.
• Results from myocardial oxygen demand-supply mismatch.
• Manifests as chest pressure, tightness, or pain that is reliably produced by exertion and
relieved by rest or nitroglycerin.
• Occurs due to a fixed atherosclerotic plaque obstructing >70% of the coronary artery
lumen that limits blood flow during exertion.
• Stable (fixed) atherosclerotic plaque characteristics:
▪ No plaque ulceration
▪ No thrombus
▪ Usually with ST depression on ECG.
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Acute Coronary Syndromes
• Unstable atheromatous plaque → plaque rupture → thrombus formation.
▪ Subtotal occlusion:
▪ Unstable angina
▪ Non-ST elevation myocardial infarction
▪ Total occlusion (100%):
▪ ST-elevation myocardial infarction (STEMI)
• Characters of unstable atheromatous plaque:
✓ Thin fibrous cap → ulcerate → rupture → thrombosis → MI.
▪ Activated macrophages in atheroma → metalloproteinase → collagen
degradation → intimal inflammation → ulceration.
▪ STATINS decrease this inflammation and are useful in ACS to stabilize the plaque.
✓ Rich lipid core → rupture.
Unstable angina
• Thrombosis with incomplete coronary artery occlusion.
• +/- ST depression and/or T-wave inversion on ECG.
• No cardiac biomarker elevation (unlike NSTEMI).
• ↑ in frequency or intensity of chest pain or any chest pain at rest.
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Extent of Ischemia
• Transmural ischemia:
✓ Occurs with complete 100% flow obstruction (STEMI)
• Subendocardial ischemia:
✓ Occurs with flow obstruction but some distal blood flow.
✓ Stable angina, unstable angina, NSTEMI
Vasospastic angina (also known as Prinzmetal or Variant)

• Occurs at rest 2° to coronary artery spasm.
▪ Midnight to early morning.
▪ Sometimes symptoms improve with exertion
• Smoking is a risk factor; hypertension and hypercholesterolemia are not.
• Triggers include cocaine, alcohol, and triptans.
• Transient ST elevation on ECG. Normal cardiac enzymes. Ergonavine provocative test.
• Treat with Ca2+ channel blockers, nitrates, and smoking cessation (if applicable).
• Avoid propranolol (nonselective blocker) → can cause unopposed alpha stimulation →
Symptoms may worsen.
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Coronary steal syndrome

• Distal to coronary stenosis, vessels are maximally dilated at baseline.
• Administration of vasodilators (eg, dipyridamole, regadenoson) dilates normal vessels →
blood is shunted toward well-perfused areas → ischemia in myocardium perfused by
stenosed vessels.
• Principle behind pharmacologic stress tests with coronary vasodilators.
Sudden cardiac death

• Death from cardiac causes within 1 hour of onset of symptoms.
• Most commonly due to a lethal arrhythmia (eg, VF) which is associated with:
➢ CAD (up to 70% of cases)
➢ Cardiomyopathy (hypertrophic, dilated).
➢ Hereditary ion channelopathies (eg, long QT syndrome, Brugada syndrome).
• Prevent with implantable cardioverter defibrillator (ICD).
Myocardial infarction
• Most often due to rupture of coronary artery atherosclerotic plaque → acute thrombosis.
• ↑ Cardiac biomarkers (CK-MB, troponins) are diagnostic.
• Commonly occluded coronary arteries: LAD > RCA > circumflex.
• Symptoms: diaphoresis, nausea, vomiting, severe retrosternal pain, pain in left arm and/or
jaw, shortness of breath, fatigue.
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• How much time does it take for the cardiac muscle to stop after the onset of total
ischemia? → 1 min.
➢ If restoration of blood < 30 min → reversible contractile dysfunction (myocardial
stunning)→ contractility gradually returning to normal over hours to days.
➢ IF restoration > 30 min → total ischemia becomes irreversible.
• Cytoplasmic hypereosinophilia is one of the earliest signs of coagulative necrosis of

myocytes.
• Neutrophils activation → fibrinous pericarditis:
1. Sharp pain increase with coughing, swallowing (d2 irritation of the posterior
pericardium).
2. Radiating to the neck (d2 irritation of the inferior pericardium to the phrenic nerve).
• Macrophages activation → phagocytosis → rupture of:
1. Free wall → cardiac tamponade.
2. Interventricular septum → VSD or shunt.
▪ Holosystolic murmur at the left sternal border 3-10 days post MI.
3. Papillary muscle → mitral regurgitation.
▪ Holosystolic murmur at the apex radiating to the axilla 3-10 days post MI.
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Evolution of myocardial infarction
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Reversible injuries in cardiac muscle
1. Myofibril relaxation→ early sign < 30 min, due to anaerobic glycolysis.

2. Disaggregation of polysomes → dissociation of rRNA from mRNA→↓protein
synthesis.
3. Disaggregation of nucleus.
4. Clumping of nuclear chromatin d2 ↓PH.
5. Triglyceride droplet accumulation d2 ↓ lipoproteins.
6. Glycogen loss→ early due to ↓ ATP.
• Mitochondrial
1. Swelling → reversible d2 ↓ATP → ↓pumps → ↑ intracellular Na & Ca.
2. Vacuolization → irreversible cell injury which indicates that the mitochondria is
permanently unable to reduce ATP.
• Contraction bands:
▪ Located at the margins of the necrotic area.
▪ Caused by reperfusion of the irreversibly damaged cells → Ca influx →
hypercontraction of the myofibrils.
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Post-infarction ventricular remodeling
• Remodeling is defined as alteration in the structure (dimensions, mass, shape) of the heart in
response to hemodynamic load and/or cardiac injury in association with neurohormonal
activation.
• Following myocardial infarction, stretched infarcted tissue increases left ventricular volume
leading to combined volume and pressure load on noninfarcted zones and
mixed concentric/eccentric hypertrophy.
• An increase in end-diastolic volume occurs early in MI to accommodate a larger preload and
compensate for the acute decrease in contractility after MI.
• Area of infarction → expansion, thinning and regional dysfunction.
• The rest → hypertrophy to compensate.
• Net result → dilated ventricular hypertrophy with enlarged LV cavity.
• Can be prevented by ACEIs or some BB.
Diagnosis of myocardial infarction

• ECG:
▪ The gold standard for MI diagnosis in the first 6 hours.
▪ ECG changes can include
➢ ST elevation (STEMI, transmural infarct), ST depression (NSTEMI,
subendocardial infarct).
➢ Hyperacute (peaked) T waves, T-wave inversion.
➢ New left bundle branch block, and pathologic Q waves or poor R wave
progression (evolving or old transmural infarct).
• Cardiac enzymes:
▪ Cardiac troponin I
➢ Rises after 4 hours (peaks at 24 hr) and is ↑ for 7- 10 days.
➢ More specific than other protein markers.
▪ CK-MB
➢ Rises after 6- 12 hours (peaks at 16- 24 hr)
➢ Predominantly found in myocardium but can also be
released from skeletal muscle.
➢ Useful in diagnosing reinfarction following acute Ml
because levels return to normal after 48 hours.
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ECG localization with STEMI
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• UW: DM increases the risk of MI by 3 times.
Complications of myocardial infarction

• Cardiac arrhythmia:
▪ Occurs within the first few days after MI.
▪ Important cause of death before reaching the hospital and within the first 24 hours
post-MI.
• Postinfarction fibrinous pericarditis:
▪ Occurs 1–3 days after MI.
▪ Friction rub.
• Papillary muscle rupture:
▪ Posteromedial papillary muscle more common to rupture due to single blood supply
from posterior descending artery.
▪ Can result in severe mitral regurgitation.
▪ Other causes of papillary rupture → bacterial endocarditis (most common cause)
• Interventricular septal rupture:
▪ Macrophage-mediated degradation → VSD → ↑ O2 saturation and pressure in RV.
• Ventricular pseudoaneurysm formation:
▪ Occurs 3–14 days after MI. Contained free wall rupture; ↓ CO, risk of arrhythmia,
embolus from mural thrombus.
• Ventricular free wall rupture:
▪ Occurs 5–14 days after MI. Free wall rupture → cardiac tamponade.
▪ LV hypertrophy and previous MI protect against free wall rupture.
▪ Acute form usually leads to sudden death.
• True ventricular aneurysm:
▪ Occurs 2 weeks to several months after MI.
▪ Outward bulge with contraction (“dyskinesia”), associated with fibrosis.
• Dressler syndrome:
▪ Occurs several weeks after MI.
▪ Autoimmune phenomenon resulting in fibrinous pericarditis.
• LV failure and pulmonary edema:
▪ Can occur 2° to LV infarction, VSD, free wall rupture, papillary muscle rupture with
mitral regurgitation.
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UW: SLE may cause an acute coronary syndrome at a young age even with angiographically
normal coronary arteries.
Special complications with MI

Inferior MI
• Right ventricular infarction → loss of right ventricular contractility.
▪ Elevated jugular venous pressure with clear lungs.
▪ Decreased preload to left ventricle → hypotension.
• Sinus bradycardia and heart block
• Hemodynamics:
▪ ↑ Right atrial pressure and CVP.
▪ ↓ CO and pulmonary capillary wedge pressure.
• Diagnosis: Right sided chest leads.
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Left main
• ST‐elevation aVR.
• Diffuse ST depressions.
Chronic myocardial ischemia

1- Hypernating myocardium
• State of chronic myocardial ischemia in which both myocardial metabolism and function are
reduced to match a concomitant reduction in coronary blood flow.
• Due to moderate/severe flow-limiting stenosis.
• This new equilibrium prevents myocardial necrosis.
• Chronically hibernating myocardium demonstrates:
1. ↓ Expression and disorganization of contractile and cytoskeletal proteins.
2. Altered adrenergic control, and reduced calcium responsiveness.
• Mechanism:
1. ↓Energy metabolism but there is sufficient ATP to prevent contracture.
2. ↑gene expression of TNF-alpha and nitric oxide synthase → inhibitors of contracture.
• These changes lead to decreased contractility and left ventricular systolic dysfunction.
• However, coronary revascularization and subsequent restoration of blood flow to
hibernating myocardium improves contractility and LV function.
2- Ischemic preconditioning
• A phenomenon in which brief repetitive episodes of myocardial ischemia followed by
reperfusion, protect the myocardium from subsequent prolonged episodes of ischemia.
• In clinical terms, repetitive episodes of angina prior to myocardial infarction can delay cell
death after complete coronary occlusion and therefore provide greater time for myocardial
salvage with coronary revascularization.
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3- Myocardial STUNNING:
• Less severe form of ischaemia-induced reversible loss of contractile function.
• Cause: brief ischemic episode (<30 min) followed by reperfusion.
• Repetitive stunning can lead to hibernation.
Differential diagnosis of chest pain
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Peripheral vascular disease
• Intermittent claudication: muscle pain, which occurs with exercise and remits with rest.
• Thigh claudication:
▪ Suggestive of occlusive disease of the ipsilateral external iliac artery or its more
distal branches (eg, common femoral, superficial femoral, profunda femoris arteries).
▪ Accompanying impotence and/or gluteal claudication suggests more proximal
aortoiliac occlusion (so-called Leriche syndrome), which, in addition to affecting
the external iliac artery, also diminishes blood flow to the internal pudendal and
gluteal branches of the internal iliac artery.
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Cardiomyopathies
Dilated cardiomyopathy
• Dilation of all four chambers of the heart. Most common cardiomyopathy (90% of cases).
• Causes:
▪ Often idiopathic or familial (Genetic mutation → usually autosomal dominant mutation
in dystrophin gene).
▪ Other etiologies include chronic Alcohol abuse, wet Beriberi, Coxsackie B viral
myocarditis, chronic Cocaine use, Chagas disease, Doxorubicin toxicity,
hemochromatosis, sarcoidosis, thyrotoxicosis, peripartum cardiomyopathy.
• Findings:
▪ HF (eccentric hypertrophy, systolic dysfunction, S3).
▪ Systolic regurgitant murmur.
▪ CXR: balloon appearance of heart.
▪ Echo: dilatation of all chambers & biventricular failure.
• Treatment:
▪ Na+ restriction, ACE inhibitors, β-blockers, diuretics, digoxin, ICD, heart transplant.
Dystrophin: which normally links the internal myocyte cytoskeleton with the external basement
membrane (Remember that dystrophin mutations are also found in the common skeletal
myopathies, i.e., Duchenne and Becker muscular dystrophies.)
• Doxorubicin DCM:
✓ Cumulative dose dependent → presents many months after discontinuation of the drug.
✓ Prevented by → DEXRAZOXANE: iron chelating agent that ↓ O2 free radicals
produced by doxorubicin.
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Hypertrophic cardiomyopathy
• Massive hypertrophy of the left ventricle.

• Causes:
▪ Usually due to genetic mutations:
➢ Autosomal dominant mutations in genes encoding sarcomeric proteins, such as
myosin binding protein C and β-myosin heavy chain.
• Clinical features include:
▪ Decreased cardiac output: LVH leads to diastolic dysfunction (ventricle cannot fill).
➢ Marked ventricular concentric hypertrophy (sarcomeres added in parallel).
o Often septal predominance.
▪ Syncope with exercise: Subaortic hypertrophy of the ventricular septum results
in functional aortic stenosis.
▪ Sudden death due to ventricular arrhythmias:
➢ HCM is the most common cause of ventricular fibrillation in individuals younger
than 30 and the most common cause of sudden cardiac death in a young athlete.
• Findings:
▪ S4, systolic murmur.
▪ May see mitral regurgitation due to impaired mitral valve closure.
• Biopsy shows myofiber hypertrophy with disarray and fibrosis.
• Treatment:
▪ Cessation of high-intensity athletics.
▪ Use of β-blocker or non-dihydropyridine Ca2+ channel blockers (eg, verapamil).
▪ ICD if patient is high risk.
• Physiology of HOCM:
▪ Asymmetric septal hypertrophy and systolic anterior motion of mitral valve → outflow
obstruction → dyspnea, possible syncope.
• Other causes of concentric LV hypertrophy: chronic HTN, Friedreich ataxia.
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• Murmur of HOCM:
▪ The degree of LVOT obstruction (and intensity of the murmur) varies based on LVEDV.
▪ Mechanisms that decrease preload or afterload → ↓ LV chamber size → ↓ the separation
between the mitral valve and interventricular septum → increasing obstruction.
▪ Sudden standing (from a sitting or supine position), Valsalva (straining phase), or nitroglycerin
administration decreases preload and will result in increased murmur intensity.
▪ In contrast, squatting (from a standing position), sustained hand grip, or passive leg raise will
increase preload and/or afterload, thereby decreasing murmur intensity.
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• Medications that generally should be avoided in patients with HCM include:
✓ Vasodilators (dihydropyridine calcium channel blockers “nifedipine, amlodipine”).
✓ Nitroglycerin and ACE inhibitors, which decrease systemic vascular resistance,
leading to decreased afterload and lower LV volumes.
✓ Diuretics: which decrease LV venous filling (preload) and also result in greater
outflow obstruction.
✓ In contrast, negative inotropic agents such as beta blockers (metoprolol),
nondihydropyridine calcium channel blockers (verapamil) and disopyramide reduce
LVOT obstruction and are helpful in symptomatic patients with HCM. In addition,
beta blockers may also help reduce anginal symptoms by decreasing myocardial
oxygen demand.
• UW: B-myosin heavy chain mutation → HCM
✓ Cardiac cell cytoskeleton mutation + mitochondrial enzyme mutation→ DCM (third
of the cases are AD)
• UW: HOCM + harsh systolic murmur → d2 systolic anterior motion of the anterior leaflet
of the mitral valve to the interventricular septum which is bulged by asymmetrical
enlargement → outflow obstruction.
• Normal morphological changes in the aging heart include:
✓ ↓ Left ventricular chamber apex-to-base dimension.
✓ Development of a sigmoid-shaped ventricular septum.
✓ Myocardial atrophy with increased collagen deposition.
✓ Accumulation of cytoplasmic lipofuscin pigment within cardiomyocytes.
• UW: Lipofuscin: yellow brown pigment in the myocyte of myocytes in old age → d2
product of free radical injury and lipid peroxidation.
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Restrictive/ infiltrative cardiomyopathy
• Decreased compliance of the ventricular endomyocardial that restricts filling during diastole
• Causes:
✓ Postradiation fibrosis, Löffler endocarditis, Endocardial fibroelastosis (thick
fibroelastic tissue in endocardium of young children), Amyloidosis, Sarcoidosis,
Hemochromatosis (although dilated cardiomyopathy is more common) (Puppy
LEASH)
✓ Löfer endocarditis: associated with hypereosinophilic syndrome; histology shows
eosinophilic infiltrates in myocardium.
• Presents:
✓ Congestive heart failure.
✓ Classic finding is low-voltage EKG with diminished QRS amplitude.
• Carcinoid heart:
✓ RT sided endocardial fibrosis (endocardial thickening) → restrictive cardiomyopathy
& pulmonary stenosis.
✓ Dx: plasma serotonin, urinary 5-hydroxy indol acetic acid.
Cardiac amyloidosis
• Deposition of abnormally folded protein (B-pleated sheet conformation):
✓ Localized amyloidosis → atrial natriuretic peptide (ANP).
✓ Diffuse amyloidosis → Ig light chains.
• Localized amyloidosis:
✓ Confined to the cardiac atria (isolated atrial amyloidosis, or IAA)
✓ The incidence of IAA increases with age, reaching > 90% in the ninth decade.
✓ This is a form of senile cardiac amyloidosis which may increase the risk of atrial
fibrillation.
Constrictive pericarditis:
✓ CT scan → thickening and calcification of the pericardium.

✓ JVP → rapid and steep y descent.
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Stress-induced (takotsubo) cardiomyopathy

• Stress induced cardiomyopathy most commonly affects postmenopausal women.
• The condition is likely caused by a catecholamine surge in the setting of physical or emotional
stress (eg, death of a loved one).
▪ Catecholamines may cause microvascular spasm leading to ischemia and myocardial
stunning or they may cause direct myocardial dysfunction.
• Hypokinesis of the mid and apical segments and hyperkinesis of the basal segments of the left
ventricle, leading to systolic dysfunction and reduced ejection fraction.
• The resulting segmental LV dysfunction creates a characteristic balloon shape on
echocardiogram that mimics that of an octopus trap (takotsubo means "octopus trap" in Japanese).
• Patients typically have chest pain that can mimic a myocardial infarction and may also have
symptoms of heart failure (eg, dyspnea, lower extremity swelling).
• ECG often shows evidence of ischemia (eg, ST elevation, T wave inversion) in the anterior
precordial leads; however, coronary angiography typically reveals an absence of obstructive
coronary artery disease.
• The condition usually resolves within several weeks with supportive treatment only.
Acute myocarditis
• Causes:
▪ Viral infection: coxsackievirus, adenovirus, and influenza.
▪ Bacterial (eg, tuberculosis).
▪ Parasitic (eg, Chagas disease).
▪ Rheumatologic disease (eg, systemic lupus erythematosus, rheumatic fever).
• Histopathology:
▪ Myofibrillary necrosis accompanied by inflammatory mononuclear cell infiltrate
consisting of lymphocytes and macrophages.
• Clinical presentation:
▪ Vary significantly; many patients remain asymptomatic with subclinical infection, but
some experience severe complications including decompensated heart failure (eg,
dyspnea, fatigue, peripheral edema) due to dilated cardiomyopathy.
▪ Ventricular arrhythmias leading to sudden cardiac death can also occur.
• Complications:
▪ Sudden death (Major cause of SCD in adults < 40 years old)
▪ Arrhythmias, heart block, dilated cardiomyopathy,
HF, mural thrombus with systemic emboli.
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Heart failure
• Clinical syndrome of cardiac pump dysfunction → congestion and low perfusion.
• Clinically:
▪ Symptoms: Dyspnea, orthopnea, fatigue.
▪ Signs: S3 heart sound, rales, jugular venous distention (JVD), pitting edema.
• Systolic dysfunction:
▪ ↓ Contractility → ↓ EF, ↑ EDV.
▪ Often 2° to ischemia/MI or dilated cardiomyopathy.
• Diastolic dysfunction:
▪ Preserved EF, normal EDV; ↓ compliance (↑ EDP).
▪ Often 2° to myocardial hypertrophy.
• Drugs that decrease mortality in HF:

▪ ACE inhibitors or angiotensin II receptor blockers, β-blockers (except in acute
decompensated HF), and spironolactone.
▪ Thiazide or loop diuretics are used mainly for symptomatic relief.
▪ Hydralazine with nitrate therapy improves both symptoms and mortality in select
patients.
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LEFT-SIDED HEART FAILURE
• Symptoms:
▪ Orthopnea:
➢ Shortness of breath when supine: ↑ venous return from redistribution of blood
(immediate gravity effect) exacerbates pulmonary vascular congestion.
▪ Paroxysmal nocturnal dyspnea:
➢ Breathless awakening from sleep: ↑ venous return from redistribution of blood,
reabsorption of peripheral edema, etc.
▪ Pulmonary edema:
➢ ↑ Pulmonary venous pressure → pulmonary venous distention and transudation
of fluid.
➢ Presence of hemosiderin-laden macrophages (“HF” cells) in lungs.
➢ Treatment: (NO LIP)
o Nitrates (better than loop diuretics as 50% of patients are euvolumic or
hypovolemic), Oxygen, Loop diuretics, Inotropes, Positioning.
▪ Decreased flow to kidneys leads to activation of renin-angiotensin system.
➢ Fluid retention exacerbates CHF.
➢ Mainstay of treatment is ACE inhibitor.
• Causes:
▪ Ischemia, hypertension, dilated cardiomyopathy, myocardial infarction, and restrictive
cardiomyopathy.
RIGHT-SIDED H EART FAILURE

• Causes:
▪ Most commonly due to left-sided heart failure.
▪ Other important causes include left to-right shunt and chronic lung disease (cor
pulmonale).
• Clinically: clinical features are due to congestion:
▪ Dependent pitting edema:
➢ Due to increased hydrostatic pressure.
▪ Hepatomegaly (nutmeg liver):
➢ ↑ Central venous pressure → ↑ resistance to portal flow → painful
hepatosplenomegaly. Rarely, leads to “cardiac cirrhosis.”
▪ Jugular venous distention:
➢ ↑ Venous pressure.
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• How can LV dysfunction lead to pulmonary HTN?
1. Reactive vasoconstriction d2 venous congestion: pulmonary congestion →
↑hydrostatic pressure → capillary leak → pulmonary edema → alveolar collapse →
↓ventilation → hypoxemia → reactive VC to shunt blood to area with better
ventilation → pulmonary artery HTN.
2. Impaired NO availability & ↑ endothelin expression → dysregulation of vascular
smooth muscle tone & structural remodeling of pulmonary vasculature.
• Dilated cardiomyopathy → systolic dysfunction

• Hypertrophic cardiomyopathy → diastolic dysfunction
The athletes heart
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Shock
• Inadequate organ perfusion and delivery of nutrients necessary for normal tissue and cellular
function. Initially may be reversible but life threatening if not treated promptly.
Infective endocarditis
• Inflammation of endocardium that lines the surface of cardiac valves; usually due to
bacterial infection.
• Causes:
▪ Acute: S aureus (high virulence):
➢ Large vegetations on previously normal valves. Rapid onset.
➢ S aureus is the most common cause in IV drug abusers.
• High-virulence organism that infects normal valves, most commonly the
tricuspid. Results in large vegetations that destroy the valve.
▪ Subacute: Viridans streptococci (low virulence):
➢ The most common overall cause.
➢ It is a low-virulence organism that infects previously damaged valves (e.g.,
chronic rheumatic heart disease and mitral valve prolapse).
➢ Results in small vegetations that do not destroy the valve (subacute endocarditis)
➢ Sequela of dental procedures. Gradual onset.
➢ Damaged endocardial surface develops thrombotic vegetations (platelets and
fibrin). Transient bacteremia leads to trapping of bacteria in the vegetations;
prophylactic antibiotics decrease risk of endocarditis.
▪ Staphylococcus epidermidis:
➢ Associated with endocarditis of prosthetic valves.
▪ Streptococcus bovis:
➢ Associated with endocarditis in patients with underlying colorectal carcinoma.
▪ HACEK organisms
➢ (Haemophilus, Aggregatibacter [formerly Actinobacillus], Cardiobacterium,
Eikenella, Kingella)
➢ Associated with endocarditis with negative blood cultures.
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• Pathogenesis:
▪ The initial process is a disruption of normal endocardial surface.
▪ This occurs most commonly at the areas of maximal turbulence to blood flow in
preexisting valvular lesions, typically the atrial surface of incompetent atrioventricular
valves or the ventricular surface of incompetent semilunar valves.
▪ This is followed by focal adherence of fibrin and platelets, forming a sterile fibrin-
platelet nidus.
▪ During bacteremia from any cause, microorganisms colonize the sterile nidus on the
endothelial surface with subsequent microbial growth leading to further activation of the
coagulation system.
▪ Streptococci infect the cardiac valves with preexisting endothelial lesions.
▪ In contrast Staphylococcus aureus can adhere to damaged or normal endothelial cells
• Clinical features of bacterial endocarditis include:
▪ Fever- due to bacteremia. Progressive Fatigue (may be the presenting symptom of IE.)
▪ Murmur- due to vegetations on heart valve.
➢ Mitral valve is most frequently involved.
➢ Tricuspid valve endocarditis is associated with IV drug abuse
▪ Skin manifestations:
➢ Janeway lesions (erythematous nontender lesions on palms and soles),
➢ Osler nodes (tender lesions on fingers or toes),
➢ Splinter hemorrhages in nail bed due to embolization of septic vegetations.
▪ Anemia of chronic disease-due to chronic inflammation.
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• Laboratory findings:
▪ Positive blood cultures:
➢ Requires multiple blood cultures for diagnosis.
➢ If culture ⊝, most likely Coxiella burnetti, Bartonella spp, HACEK
▪ Anemia of chronic disease (↓ Hb, ↓ MCV; ↑ ferritin, ↓ TIBC, ↓ serum iron, and
↓ % saturation).
▪ Transesophageal echocardiogram is useful for detecting lesions on valves.
Nonbacterial thrombotic endocarditis (NBTE) (marantic endocarditis):

• Sterile platelet-rich vegetations that arise in association with a hypercoagulable state or
underlying adenocarcinoma.
• Vegetations arise on the mitral valve along lines of closure and result in mitral regurgitation.
• Libman-Sacks endocarditis
▪ Due to sterile vegetations that arise in association with SLE.
▪ Vegetations are present on the surface and undersurface of the mitral valve and result
in mitral regurgitation.
• Pathogenesis
▪ Begin with valvular endothelial injury caused by inflammatory cytokines, which triggers
platelet deposition in the presence of an underlying hypercoagulable state.
• Causes:
▪ Most commonly associated with advanced malignancy (especially mucinous
adenocarcinoma)
▪ Systemic lupus erythematosus (Libman—Sacks endocarditis)
▪ Less commonly; antiphospholipid syndrome, DIC, and extensive burns.
• Histology:
▪ NBTE vegetations consist of bland thrombus with strands of fibrin, immune complexes,
and mononuclear cells (white thrombus).
▪ The vegetations typically affect the left-sided heart valves (mitral or aortic) and are often
asymptomatic; however, systemic embolization (eg, stroke, acute limb ischemia) can
occur and is the most common presentation of NBTE.
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• Osler nodes are d2 → immune complex deposition.

• Janeway lesions is d2 → septic emboli.
• UW: Effect of IE on kidney:
✓ If microemboli → hematuria
✓ If immune complex deposition → acute diffuse proliferative GN →nephritic
syndrome→hematuria, proteinuria, red cell casts and increase in serum
creatinine.
• UW: Native valve bacterial endocarditis (NVBE)→ MVP is the most common cause
then RHD.
• UW: Tricuspid endocarditis + pleuritic chest pain → septic pulmonary emboli.
• UW: the least organ to be affected by thromboembolism of IE is LIVER d2 dual blood
supply.
• UW: cancer + NVBE → d2 hypercoagulable state caused by circulating products of
cancer which is procoagulable → e.g. in Trousseau’s Syndrome (migratory
thrombophlebitis) d2 visceral malignancy.
Rheumatic fever
Acute rheumatic fever
• Systemic complication of pharyngitis due to group A β-hemolytic streptococci; affects
children 2- 3 weeks after an episode of streptococcal pharyngitis ("strep throat").
• Caused by molecular mimicry; bacterial antigens (M protein, N-acetyl beta-D-glucusamine)
resembles proteins in human tissue (heart and CNS).
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USMLE Endpoint
• Diagnosis is based on Jones criteria:

▪ Evidence of prior group A β-hemolytic streptococcal infection (e.g., elevated ASO or
anti-DNase B titers) with the presence of major and minor criteria.
▪ Minor criteria are nonspecific and include fever and elevated ESR.
▪ Major criteria:
➢ Migratory polyarthritis: swelling and pain in a large joint (e.g., wrist, knees,
ankles) that resolves within days and "migrates" to involve another large joint.
➢ Pancarditis:
• Endocarditis: Mitral valve is involved more commonly than the aortic
valve. Characterized by small vegetations along lines of closure that lead
to regurgitation.
• Myocarditis:
o The most common cause of death during the acute phase.
o Causes cardiac dilatation → functional MR → HF, S3 gallop.
o Aschoff bodies that are characterized by foci of chronic
inflammation, reactive histiocytes with slender, wavy nuclei
(Anitschkow cells), giant cells, and fibrinoid material.
• Pericarditis: leads to friction rub and chest pain.
➢ Subcutaneous nodules.
➢ Erythema marginatum: annular, nonpruritic rash with erythematous borders,
commonly involving trunk and limbs.
➢ Sydenham chorea
• A hyperkinetic extrapyramidal movement disorder.
• The most common acquired chorea of childhood.
• Restlessness and purposeless jerking movements.
• Latency 2-3 months after sore throat.
• Dx by antineural Abs binding to caudate and subthalamic nuclei.
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• Acute attack usually resolves but may progress to chronic rheumatic heart disease; repeat
exposure to group A p-hemolytic streptococci results in relapse of the acute phase and increases
risk for chronic disease.
• Rx: Aschoff body→ focal areas of interstitial inflammation characterized by
✓ Fragmented collagen.
✓ Mononuclear (antischkow’s cells)
✓ Multinucleated giant cells (aschoff cells).
CHRONIC RHEUMATIC HEART DISEASE

• Valve scarring that arises as a consequence of rheumatic fever.
• Results in stenosis with a classic 'fish-mouth' appearance:
▪ Almost always involves the mitral valve; leads to thickening of chordae tendineae
and cusps.
▪ Occasionally involves the aortic valve; leads to fusion of the commissures.
▪ Other valves are less commonly involved.
• Complications include infectious endocarditis.
Acute pericarditis
• Inflammation of the pericardium [A, red arrows].
• Commonly presents with sharp pain, aggravated by inspiration, and
relieved by sitting up and leaning forward.
• Often complicated by pericardial effusion [between yellow arrows
in A]. Presents with friction rub.
• ECG changes include widespread ST-segment elevation and/or
PR depression.
• Causes include idiopathic (most common; presumed viral),
confirmed infection (eg, coxsackievirus B), neoplasia, autoimmune
(eg, SLE, rheumatoid arthritis), uremia, cardiovascular (acute STEMI or Dressler syndrome),
radiation therapy.
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• Triphasic friction rub (occurring during atrial systole, ventricular systole, and early ventricular
diastole) on cardiac auscultation; however, the rub can be absent if significant pericardial
effusion is present.
Types of acute pericarditis

• Fibrinous pericarditis:
▪ The most common type of pericarditis.
▪ Characterized by pericardial inflammation with a serous, fibrin-containing exudate in
the pericardial space.
▪ Common causes include viral infection, myocardial infarction, uremia, and
rheumatologic disease (eg, systemic lupus erythematosus, rheumatoid arthritis).
• Hemorrhagic pericarditis:
▪ Malignancy & TB.
▪ Following cardiac surgery, or in patients with underlying coagulopathy.
• Purulent pericarditis:
▪ Results from active bacterial infection (eg, Staphylococcus aureus, Streptococcus) in the
pericardial space, which may occur due to hematogenous spread or direct extension of
pneumonia or endocarditis.
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USMLE Endpoint
Constrictive pericarditis
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Cardiac tamponade
• Compression of the heart by fluid (eg, blood, effusions [arrows in A] in pericardial space) →
↓CO.
↑ HR
• Equilibration of diastolic pressures in all 4 chambers.

• Pulsus paradoxus
1. ↓ in amplitude of systolic BP by > 10 mm Hg during inspiration.
2. Seen in cardiac tamponade, asthma, obstructive sleep apnea, pericarditis, croup.
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• UW: Case: mild respiratory illness one week ago, hypotension, tachycardia, JVD, pulse
undetected during inspiration, lungs are clear on auscultation.
➢ Dx→ cardiac temponade d2 serous viral pericarditis.
• NB: Differential diagnosis of (acute JVD + hypotension + tachycardia)
➢ Cardiac tamponade→ clear lung on auscultation.
➢ Tension pneumothorax → diminished air entry.
➢ Why not fibrinous pericarditis→ pleuritic chest pain + friction rub.
➢ Why not constrictive pericarditis→ requires month to years to produce cardiac
tamponade.
Syphilitic heart disease

• 3° syphilis disrupts the vasa vasorum of the aorta with consequent atrophy of vessel wall
and dilatation of aorta and valve ring.
• May see calcification of aortic root, ascending aortic arch, and thoracic aorta. Leads to “tree
bark” appearance of aorta.
• Can result in aneurysm of ascending aorta or aortic arch, aortic insufficiency.
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Cardiac tumors
• Most common heart tumor is a metastasis (eg, melanoma).
Myxomas
• Most common 1° cardiac tumor in adults (arrows in A).
• 90% occur in the atria (mostly left atrium).
• Myxomas are usually described as a “ball valve” obstruction in the left atrium (associated with
multiple syncopal episodes).
• May auscultate early diastolic “tumor plop” sound.
• Histology:
▪ scattered cell in mucopolysaccharide stroma + abnormal BVs, hmge.
▪ gelatinous material, myxoma cells immersed in glycosaminoglycans.
Rhabdomyomas
• Most frequent 1° cardiac tumor in children (associated with tuberous sclerosis).
• Histology: hamartomatous growths.
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Valvular Disease
• Introduction – mechanical degeneration the leading cause of valvular heart disease in the US,
RF in the developing world.
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Aortic Stenosis
• Systolic murmur due to turbulence as blood hits stenotic aortic valve.
• Causes:
1) Mechanical: wear and tear resulting in dystrophic calcification (calcific degeneration
the most common cause).
2) Chronic rheumatic fever: characterized by fusion of valve commissures, but more
likely to damage the mitral valve, both types most common in elderly patients.
3) Congenital: unicuspid or bicuspid defects in pediatric patients.
• Presentations
1) Asymptomatic until very advanced.
2) Rapid progression once symptomatic (within 5 years).
3) Elderly patient (>60) or younger patient with bicuspid aortic valve, presents with
exertional angina due to decreased coronary perfusion.
4) Exertional syncope and dyspnea (the heart is unable to adequately increase cardiac
output during exercise).
5) Concentric LV hypertrophy leading to CHF.
• Auscultation findings:
1) Paradoxically Split S2:
▪ Normal split S2 is during inspiration due to delayed pulmonic valve closure.
▪ When aortic valve is stenotic, it closes later than normal, producing a single S2
sound on inspiration (closing of the valves aligns), and a spilt S2 on expiration
due to the aortic valve closing late.
2) Crescendo-Decrescendo Systolic Murmur:
▪ Classically heard in 2nd right intercostal space with radiation to carotids.
▪ Peaks in early systole (the later the peak in systole, the more advanced the
stenosis).
▪ Decreased preload decreases murmur intensity (less blood passing through
stenotic valve), an ejection click may be heard (“ejection-type systolic murmur”).
3) Pulsus Parvus et Tardus:
▪ Weak and late pulse due to pressure lost traversing the stenotic valve.
▪ Ejection velocity of blood increased due to same amount of blood needing to
pass through a smaller valve area (speed directly proportional to degree of
stenosis).
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Pulmonic Stenosis
• Similar to aortic Stenosis, but softer due to lower pressure in pulmonic circuit, uncommon.
Aortic Regurgitation
• Diastolic murmur due to blood shooting back through aortic valve during diastole.
• Causes:
• Presents with:
1) Worsening exertional dyspnea.
2) Orthostatic hypotension.
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• Auscultation findings in AR:
1) Early diastolic, blowing, long decrescendo murmur.
2) Heard at the left sternal border.
Austin flint murmur:

• Low-pitched mid to late diastolic rumble heard best at the apex of the heart and is
associated with severe aortic regurgitation.
• Aortic valve so regurgitant that blood jets back into the left ventricle, hits anterior
leaflet of mitral valve or regurgitates into the LA.
• Other Signs of AR:

1) Head bobbing with heart beats (due to wide pulse pressure).
2) Corrigan’s pulse (carotid pulse with rapid rise and fall).
3) Hyperdynamic (“water hammer”) pulse.
4) Femoral bruits on compression of femoral pulse.
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Pulmonic Regurgitation
• Diastolic murmur.
• Similar to Aortic Insufficiency/Regurgitation, but softer due to lower pressure in pulmonic
circuit, uncommon.
Mitral Stenosis
• Most commonly caused by rheumatic fever.
• Presents with:
✓ Exertional dyspnea, arrhythmias, orthopnea.
✓ Severe MS → LA dilation:
▪ Alter conduction → produce AFIB.
▪ Compress esophagus resulting in dysphagia for solids but not liquids,
compress the left recurrent laryngeal nerve resulting in hoarseness (Ortner
Syndrome).
✓ Pulmonary congestion.
✓ Infective endocarditis (late and highly specific sequela).
✓ Mid-Diastolic Rumble:
▪ Mid-to-late diastolic murmur heard after OS.
✓ Opening Snap (OS):
▪ Click that corresponds to abrupt halt in valve leaflet motion in diastole after
rapid opening due to fusion of leaflet tips. Best heard at apex.
▪ Time between A2 and OS inversely correlated with severity.
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• Hemodynamics in mitral stenosis:
✓ Pressure is propagated proximally to the stenosis → ↑ PCWP.
✓ Pressure not increased past the stenosis → LVEDP is typically normal.
✓ Transmitral gradient elevated.
Mitral Valve Prolapse (MVP)

• Systolic murmur, redundant valve tissue results in bulging of one or both leaflets into LA
during systole, possible regurgitation also.
• Causes:
1. Abnormal valvular growth: excess production of valve substance (dermatan sulfate).
2. Chronic rheumatic fever.
3. Myxomatous degeneration.
4. Chordae tendineae rupture.
5. Usually isolated abnormality, but may be associated with Marfan’s Syndrome,
Ehlers-Danlos Syndrome, ASD.
• Presentations
1. Most patients asymptomatic.
2. If symptoms, presents with palpitations, chest pain (not associated with CAD or MI),
exertional dyspnea, fatigue, cough, orthopnea.
3. Rarely presents as a panic disorder, may palpate thrill over chest wall.
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1. Mid-Systolic Click:
▪ Due to sudden tensing of chordae tendineae.
▪ Decreased preload moves click closer to S1.
▪ Best heard over apex, loudest just before S2, usually benign.
2. Late Systolic Crescendo Murmur: if regurgitation present.
• Complications include risk of chordae tendineae rupture.
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Mitral Regurgitation
• Systolic murmur, retrograde blood flow into LA that occurs throughout systole, leading to
increased LVEDV and increased LA volume.
• Late manifestations in chronic disease include LA dilation and LV dilation and hypertrophy.
• Causes:
1. Chronic rheumatic fever/Infective Endocarditis.
2. Chordae Tendineae Rupture.
3. Mitral Valve Prolapse.
4. Ischemic Heart Disease: post MI.
• Presents with:
1. Dyspnea, orthopnea, fatigue.
2. Symptoms occur if regurgitation develops acutely or if atria can no longer
compensate in chronic disease.
1. Holosystolic/ Pansystolic Murmur: loudest at apex, radiates to axilla, best heard
with patient in left lateral decubitus position, does not change with inspiration
(contrast Tricuspid Insufficiency/Regurgitation, which increases during inspiration).
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Tricuspid Regurgitation
• Systolic murmur, retrograde blood flow into RA that occurs throughout systole, similar to
Mitral Regurgitation/Insufficiency, but softer due to lower pressure in pulmonic circuit.
• Causes:
1. Carcinoid Heart Disease: symptoms begin when GI tumor metastasizes to liver
(any hormones produced distal to liver in venous system metabolized by MAO in
lungs), produces 5-HT which fibroses tricuspid and pulmonary valves.
2. IV Drug Use: results in right heart endocarditis (S. aureus).
• Presents with:
1. Pulsatile liver due to increased venous pressures behind the right heart.
1. Holosystolic/Pansystolic Murmur: increased intensity during inspiration due to
increased venous return to the right heart.
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Vasculitis
❖ BASIC PRINCIPLES:
• Etiology is usually unknown; most cases are not infectious.
• Clinical features include:
▪ Nonspecific symptoms of inflammation (e.g., fever, fatigue, weight loss, and myalgias).
▪ Symptoms of organ ischemia- due to luminal narrowing or thrombosis of the inflamed vessels.
• Divided into large-, medium-, and small-vessel vasculitides.
▪ Large-vessel vasculitis involves the aorta and its major branches.
▪ Medium-vessel vasculitis involves muscular arteries that supply organs.
▪ Small-vessel vasculitis involves arterioles, capillaries, and venules.
LARGE-VESSEL VASCULITIS
1- Temporal (Giant Cell) Arteritis
• Granulomatous vasculitis that classically involves branches of the carotid artery.
• Most common form of vasculitis in older adults (> 50 years); usually affects females.
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• Biopsy:
▪ Inflamed vessel wall with giant cells and intimal fibrosis.
▪ Lesions are segmental; diagnosis requires biopsy of a long segment of vessel,
and a negative biopsy does not exclude disease.
• Tocilizumab:
▪ Can be used with corticosteroids.
▪ Production of IL-6 is highly associated with severity of the disease.
• Polymyalgia rheumatica:
▪ Pain and stiffness in shoulders and hips.
▪ Does not cause muscular weakness.
▪ Fever, malaise, weight loss.
▪ Associated with giant cell (temporal) arteritis.
▪ ↑ ESR, ↑ CRP, normal CK.
▪ Rapid response to low-dose corticosteroids
2- Takayasu Arteritis
• Granulomatous vasculitis that classically involves the aortic arch at branch points.
• Presents in adults< 50 years old (classically, young Asian females) ('pulseless disease').
• Treatment is corticosteroids.
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USMLE Endpoint
MEDIUM-VESSEL VASCULITIS
1- Polyarteritis Nodosa
• Necrotizing vasculitis involving multiple organs; lungs are spared.
• Usually middle-aged men.
• Associated with serum HBsAg.
• Biopsy:
▪ Lesions of varying stages are present.
▪ Early lesion consists of transmural inflammation with fibrinoid necrosis;
eventually heals with fibrosis, producing a 'string-of-pearls' appearance on imaging.
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2- Kawasaki Disease
• Classically affects Asian children < 4 years old.
• Presentations: fever for >5 days plus 4 of the following findings:
▪ Bilateral non-exudative conjunctival injection (erythema).
▪ Cervical lymphadenopathy
▪ Mucositis:
o Erythema of the palatine mucosa,
o Fissured erythematous lips
o "Strawberry" tongue.
▪ Extremity changes:
o Edema of hands and feet.
o Erythema of palms and soles, desquamation of the fingertips (periungual).
▪ Rash: Polymorphous (usually urticarial) erythematous rash on the extremities that
spreads centripetally to the trunk.
▪ A serious complication of Kawasaki disease is coronary artery inflammation leading
to the development of coronary artery aneurysms.
• Treatment is aspirin and IVIG; disease is self-limited.
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3- Buerger Disease
• Segmental vasculitis that extend into contiguous veins and nerves.

• Necrotizing vasculitis involving digits.
• Highly associated with heavy smoking → hypersensitivity to intradermal tobacco injection.
• Treatment is smoking cessation.
SMALL-VESSEL VASCULITIS
1- Wegener Granulomatosis
• Presentations:
1. Upper respiratory tract: perforation of nasal septum, chronic sinusitis, otitis media,
mastoiditis.
2. Lower respiratory tract: hemoptysis, cough, dyspnea.
3. Renal: hematuria, red cell casts.
• Biopsy Triad:
1. Focal necrotizing vasculitis.
2. Necrotizing granulomas in the lung and upper airway.
3. Necrotizing glomerulonephritis.
• PR3-ANCA/c-ANCA (anti-proteinase 3) levels correlate with disease activity.
• Treatment is cyclophosphamide and steroids; relapses are common.
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2- Microscopic Polyangiitis
• Necrotizing vasculitis involving multiple organs, especially lung and kidney.
• Presentation is similar to Wegener granulomatosis, but nasopharyngeal involvement and
granulomas are absent. Palpable purpura can be present.
• Serum MPO-ANCA/p-ANCA (anti-myeloperoxidase) levels correlate with disease activity.
• Treatment is corticosteroids and cyclophosphamide; relapses are common.
3- Behçet syndrome
• High incidence in Turkish and eastern Mediterranean descent.
• Recurrent aphthous ulcers, genital ulcerations, uveitis, erythema nodosum.
• Can be precipitated by HSV or parvovirus.
• Flares last 1–4 weeks.
• Immune complex vasculitis.
• Associated with HLA-B51.
4- Eosinophilic granulomatosis with polyangiitis

(Churg-Strauss Syndrome):
• Necrotizing granulomatous inflammation with eosinophils involving multiple organs,
especially lungs and heart.
• Asthma and peripheral eosinophilia are often present.
• Other symptoms:
1. Sinusitis, skin nodules or
2. Palpable purpura, peripheral neuropathy (eg, wrist/foot drop).
3. Can also involve heart, GI, kidneys (pauciimmune glomerulonephritis).
• Serum p-ANCA levels correlate with disease activity. ↑ IgE.
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USMLE Endpoint
5- Henoch-Schonlein Purpura (HSP) (IgA vasculitis)
• Vasculitis due to IgA immune complex deposition; most common vasculitis in children.
• Disease is self-limited, but may recur; treated with steroids, if severe.
• UW: intranasal ulcer + oliguria → Wegener.

• UW: Late onset asthma + inability to dorsiflex wrist + eosinophilia --> churg struss.
characterized by late-onset asthma, rhinosinusits and eosinophilia. Peripheral nerve
involvement (eg, mononeuntis multiplex) frequently occurs as a result the associated
vasculitis affecting the epineural vessels.
Varicose veins:
• Varicose veins are dilated, tortuous veins resulting from impairment of the venous valves and
reflux of venous blood.
• This leads to venous stasis/congestion edema and an increased incidence of superficial venous
thrombosis.
• Thromboembolism is a very infrequent complication of varicose veins while venous stasis
ulcers are very common and often occur over the medial malleolus.
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Venous stasis dermatitis
• UW: Phlegmasia alba dolens (painful white leg. "milk leg") is a consequence of
iliofemoral venous thrombosis occurring in peripartum women. Pregnancy predisposes to
deep venous thrombosis due to the pressure of the gravid uterus on deep pelvic veins
(producing venous stasis) as well as increased hypercoagulabilrty.
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lightening related complications
• UW: Alveolar cells containing golden cytoplasmic granules that turn dark blue with
Prussian blue staining?
1. Dx→ “hemosiderin-laden macrophages”
2. NB: Prussian blue detects iron (hemosiderin)
• NB: golden yellow cytoplasmic granules or brown pigment is one of two options
1. Hemosiderin → detected by Prussian blue pigment.
2. Lipofuscin → NOT detected by Prussian blue.
• UW: Persistent lymphedema (with chronic dilatation of lymphatic channels) predisposes to
the development of Iymphangiosarcoma, a rare malignant neoplasm of the endothelial
lining of lymphatic channels. This cancer may arise approximately 10 years after radical
mastectomy with axillary lymph node dissection for breast cancer.
• UW: A 23-year-old Caucasian male who notes recurrent severe nosebleeds is found to
have pink spider-like lesions on his oral and nasal mucosa, face and arms. The patient
most likely suffers from?
1. Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia) is an
autosomal dominant condition marked by the presence of telangiectasias in the skin
as well as the mucous membranes of the lips. Oronasopharynx, respiratory tract,
gastrointestinal tract and urinary tract. Rupture of these telangiectasias may
cause epistaxis, gastrointestinal bleeding or hematuria.
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Mediastinal pathology
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CVS PHARMACOLOGY
Hypertension treatment
• UW: the most effective long term ttt option of HF + HTN → ACEIs → they inhibit
myocardial remodeling and the associated deterioration of ventricular contraction function.
Also BB.
• UW: ttt of isolated systolic htn in old patient→if
1. Diabetic → ACEIs.
2. Non-diabetic→ CCBs (amlodipine) or thiazide.
Loop diuretics
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Thiazide diuretics
Potassium sparing diuretics
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Diuretics: electrolyte changes
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ACE inhibitors
• UW: first-dose hypotension can be a potential limiting factor when initiating ACE
inhibitors. Significant hypotension is most likely to occur in patients with high plasma
renin activity, such as those with volume depletion (eg. from diuretic use) or heart failure.
Initiation of ACE inhibitor therapy causes abrupt removal of the vasoconstrictive effects of
angiotensin II, resulting in decreased peripheral vascular tone and a precipitous drop in
blood pressure in susceptible patients. To prevent the development of first-dose
hypotension, therapy should be started at low doses and slowly titrated upward as
needed.
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Angiotensin II receptor blockers
Aliskiren
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UW: nitrates cause myosin light chain dephosphorylation.

K: Theophylline is adenosine receptor blocker by preventing the bronchospastic effect of
adenosine.
UW: Increased levels of cGMP lead to decreased activity of myosin light-chain kinase and
myosin light chain dephosphorylation; resulting in vascular smooth muscle relaxation.
UW: cAMP increases the conductance of the calcium channels in the sarcoplasmic reticulum, and
as a result more calcium can enter the cell and strengthen the force of contraction. Thus the
inhibition of phosphodiesterase isoenzyme 3 by milrinone can increase cardiac contractility.
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Calcium channel blockers

,
UW: the most frequent side effect of verapamil is *constipation *gingival hyperplasia *heart block.
UW: subacharanoid hmge generates substances from blood clots that → cerebral vasospasm →
altered mental status and -focal neurological deficit 7-10 days after SAH.
*prevented by nimodipine.
UW: Nifedipine causes peripheral vasodilatation which may result in reflex tachycardia.
Therefore this antihypertensive drug is useful for patients with bradycardia.
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Beta blockers
• UW: Beta blockers lower blood pressure via 2 mechanisms:

1. Reducing myocardial contractility and heart rate.
2. Decreasing renin release by the kidney.
• UW: After initial stabilization, beta blockers (eg. carvedilol, metoprolol) should be started
in all HF patients with left ventricular (LV) systolic dysfunction to improve survival.
Beta blockade decreases cardiac work by:
1. Slowing the ventricular rate.
2. It also reduces peripheral resistance (afterload) by decreasing circulating levels of
vasoconstricting hormones (eg. norepinephrine, renin, endothelin).
Beta blockers should not be initiated in patients with unstable HF and should be
introduced slowly to avoid worsening of the patient's condition by further impairing
cardiac output.
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Hydralazine
• UW: although direct arteriolar vasodilators like hydralazine and minoxidil are effective in
lowering blood pressure they often cause reflex tachycardia and edema. Due to these
bothersome side effects, these agents are rarely used first line and are usually reserved for
patients with severely uncontrolled hypertension who are resistant to other drugs. To help
mediate these side effects, these agents are often given in combination with
sympatholytics and diuretics.
Hypertensive emergency
• UW: ttt of postoperative HTN → esmolol → short acting & easily reversible.
*ttt of HTN + renal insufficiency → Fenoldopam → the only available IV agent that
improves renal perfusion while it lowers BP.
• K: nitruprusside → ↓TPR in arteries and veins so used in htn emergency (the DOC used
IV).
• Side effect → cyanide poisoning which is treated by:
▪ Nitrites → produce methaemoglobin which binds the cyanide → cyanomethemoglobin.
▪ Thiosulfate→ convert cyanomethemoglobin to methemoglobin.
Nitrates
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• UW: nitrates → venodilator → ↓preload → ↓LV volume during diastole which is the main
effect in stable angina.
• NB: nitrates are venodilator in low dose, but in high dose → arteriolodilator → ↓ afterload
but it also ↓coronary flow.
• UW: which nitrate has the highest bioavailability if given oral? → Isosorbide mononitrate.
• UW: Nitrates must be avoided in:
- patients with hypertrophic cardiomyopathy (due to increased outflow tract obstruction).
-right ventricular infarction (due to reduction in preload, impairing cardiac output).
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-those on phosphodiesterase inhibitors (synergism increases the risk of severe
hypotension).
• K: tackyphylaxis of nitrates (receptor downregulation): people who use the patch should
remove it at night to prevent tackyphylaxis. Due to → depleted glutathione stores.
Antianginal therapy
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Ranolazine
• Mechanism:
▪ Inhibits late sodium current.
▪ Reduces calcium overload “which causes high wall tension” → Reduces wall tension and O2
demand.
• Clinical use:
▪ Angina refractory to other medical therapies.
• Adverse effects:
▪ Constipation, dizziness, headache.
▪ QT prolongation (blockade of K channels)
Milrinone
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• K: potassium channel openers: minoxidil & diazoxide.

▪ Mechanism: ↑ K efflux → hyperpolarization of smooth muscle → arteriolodilator.
▪ Uses:
1. HTN emergency → diazoxide (↓insulin release, so used also in ttt of
insulinoma).
2. Severe HTN → minoxidil (hypertrichiosis, so used also in baldness)
• UW: Energy for myocardium is coming from 3 sources:
▪ Glycolysis.
▪ Glucose oxidation→less O2 consumption.
1. produce more ATP but requires more O2
▪ Fatty Acid Oxidation inhibitors→ newer drugs for ttt of angina aiming to shift
from FA oxidation to glucose oxidation.
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Lipid lowering agents
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• UW: Statins: *stop if ALT > 3 times upper normal limit.

✓ Liver function tests are recommended before starting attain therapy; BUT routine
monitoring isn’t recommended unless signs of liver dysfunction develop (fatigue,
malaise, anorexia)
✓ Most hepatotoxicity is within 3 months.
• UW: Case: patient with angina taking the following medications metoprolol, atorvastatin,
aspirin coming to the ER with muscle pain, fatigue, dark urine and acute renal failure. What
medication did he take? → Enzyme inhibitor that enhance the action of atorvastatin causing
these manifestations of rhabdomyolysis.
• NB: Statins are metabolized by CYP 450 3A4 except pravastatin.
• UW: Case: H/O MI + low HDL → what is the most effective therapy preventing future
CVS events? → STATINS NOT niacin!
“Patients with ↓HDL have high risk CVS events. Non-pharmacological measures such as
exercise and weight loss and smoking cessation have significant CVS benefits”
“In contrast, use medications to raise HDL doesn’t improve CVS outcomes. Statins are
indicated for 2ry prevention in all patients with known CVS disease regardless of baseline
lipids”
• K: Why statins cause Rhabdomyolysis? → d2 ↓mevalonic acid →↓farnesyl ppi → ↓CoQ

→ ↓electron transport chain →↓ATP → ↓Na & K pumps → cell swelling → rupture.
• UW: All statins are metabolized by P450 except pravastatin.
• UW: ↑TG is treated by (Fibrates + niacin + omega 3 fatty acids in fish oil).
• UW: cholestyramine → ↓enterohepatic circulation → ↑bile acid synthesis from cholesterol
d2 ↑HMG CoA reductase → ↑cholesterol → gallbladder stones.
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This effect can be blocked by adding statins to cholestyramine.
BUT cholestyramine ↓absorption of statins, so administered 4 hours apart.
• UW: The antilipid drug that ↑TG is cholestyramine.
• UW: side effects of niacin: → 5 H:
o Hot flush→ use aspirin.
o hyperglycemia→acanthosis nigricans
o hyperuricemia→precipitate gout.
o hepatitis.
o Harsh (pruritis).
• UW: niacin has a vasodilatory effect and can potentiate the antihypertensive therapy, so
adjust the dose
• UW: 2 combinations to avoid:
o Statins + fibrates → ↑myopathy.
o Cholestyramine + fibrates → gallstones.
• UW: HTN + Dyslipidemia → DON’T USE BB or Thiazides → ↑lipids.
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Cardiac glycosides
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• UW: the dose of digoxin must be reduced in elderly patients even if normal creatinine → as
digoxin is cleared by the kidney and elderly exhibit age-related renal insufficiency.
• UW: The initial cellular event triggering digoxin response → ↓Na efflux
• UW: Digoxin toxicity → delayed after repolarization via ↑Ca → ventricular tachycardia
→ death.
• K: digitalis is used in all SVT except WPW syndrome as it ↑ conduction in the accessory
pathway.
• UW: The best BB in HF is Carvedilol.
• UW: medications with –ve inotropic action (↓HR):
1. BB, CCBs
2. Digoxin
3. Amiodarone and sotalol
4. Cholinergic agonists → pilocarpine & rivastigmine.
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Antiarrhythmics:
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174
• K: Quinidine has also:

✓ Muscarinic receptor antagonist→↑HR, ↑AV conduction→so need initial
digitalization before use in AF. &↑QRS&↑QT.
✓ Alpha blocking activity→ Vasodilatation → reflex tachycardia.
• K: Procainamide→ hematotoxic → thrombocytopenia & agranulocytosis.
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• UW: Class 1C drugs are the slowest of the class 1 agents to dissociate from the sodium
channel. This results in a phenomenon known as use-dependence, in which their sodium
blocking effects intensify as the heart rate increases due to less time between action
potentials for the medication to dissociate from the receptor.
Class I Intermediate binding to Na channels but also blocks K. ↓V max & ↑APD
Class II Rate of binding and release is so rapid → no change in No V max & ↓APD
Vmax. Since they block Na window current → ↓APD.
Class Very tight binding & slow release. ↓↓↓V max & no effect on APD
III
• UW: class 1 antiarrhythmic medications:
▪ Preferentially bind to and block activated and inactivated voltage-gated sodium
channels in cardiac pacemaker cells and myocytes.
▪ Dissociation of the drug from the channel occurs during the resting state; a
conformational state distinct from the inactivated state that occurs following
repolarization.
▪ Class 1 antiarrhythmic exhibit use dependence; a phenomenon in which tissues
undergoing frequent depolarization become more susceptible to blockage. Use
dependence occurs because the sodium channels in rapidly depolarizing tissue spend
more time in the activated and inactivated states, thus allowing more binding time
for the drug.
▪ For class 1 antiarrhythmics, sodium-channel-binding strength is 1C > 1A > 1B.
• Use dependence is more pronounced in class 1C antiarrhythmics because of their slow
dissociation from the sodium channel, which allows their blocking effects to accumulate
over multiple cardiac cycles.
▪ This effect is enhanced with tachycardia and the resulting increase in sodium
channel blockade helps to slow conduction speed and terminate tachyarrhythmias.
-The prominent use dependence effects of class 1C drugs can cause a delay in
conduction speed that is out of proportion to prolongation of the refractory period.
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This can promote arrhythmias, especially in patients with ischemic or structural heart
disease.
• Class 1B antiarrhythmics (eg. lidocaine, mexiletine, and tocainide) bind less avidly to
sodium channels than the other class 1 antiarrhythmics. Dissociation from the channels
occurs so rapidly that there is minimal cumulative effect over multiple cardiac cycles,
resulting in little use dependence. These drugs are more selective for ischemic
myocardium because the reduced resting membrane potential delays sodium channel
transition from the inactivated to the resting state, resulting in increased drug-channel
binding. Class 1B antiarrhythmics are useful for treating ischemia-induced ventricular
arrhythmias, one of the most common causes of death in the short term following acute
myocardial infarction.
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• UW: Drug that prolongs both PR & QT interval → Sotalol.

• UW: Drug with QRS prolongation + little effect on QT → class Ic
✓ QRS prolongation means in phase 0 → Na blocking activity → class I
✓ Little effect on QT → minimal effect on APD.
• UW: Drug that prolongs QT interval without the risk of torsade de point → Amiodarone.
NB: Drugs that prolongs QT interval → class Ia & III
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178
• NB: BB has no effect on QT.
• UW: drug that prolong QT & prolong PR intervals → Sotalol.
• UW: Drugs causing Torsade’s de point:
▪ Verapamil
▪ metoprolol
▪ sotalol
▪ lidocaine
▪ digoxin.
• UW: ttt of WPW Syndrome → Amiodarone & procainamide.
• UW:
▪ Class Ic → exhibit strong use dependence → prolongs QRS at high HR “normally,
QRS decrease when HR increase”.
▪ Class III → exhibit reverse-use dependent → prolongs QT at slow HR.
• UW: Drug that ↓HR but has no effect on myocardial contractility or relaxation →
Ivabradine.
▪ Ivabradine → inhibit Naf channels → prolonging phase IV (slow depolarization
phase) → ↓HR.
▪ Ivabradine is a –ve chronotropic with no effect on contractility or relaxation.
Uses: used in chronic HF with ↓EF + persistent symptoms despite appropriate ttt.
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Ivadrabine
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me/USMLEEndopoint USMLE Endpoint

Embryonic Structure Gives RISE TO:

• Truncus arteriosus → Ascending aorta and pulmonary trunk.

Septation of the chambers:

Patent foramen ovale:

1. Muscular ventricular septum forms. Opening is called interventricular foramen.

Aorticopulmonary septum: (Spiral Septum)

Abnormal AP septum (conotruncal abnormalities):

• Aortic/pulmonary: derived from endocardial cushions of outflow tract.

Congenital heart diseases

Right-to-left shunts (cyanotic heart diseases)

1- Persistent truncus arteriosus

5- Total anomalous pulmonary venous return

7- Complete AV canal defect:

Right to left shunts (Acyanotic heart diseases)

1- Ventricular Septal Defect (VSD)

Secundum type ASD:

3- Patent ductus arteriosis

• Ductus arteriosus shunts blood in utero: Left pulmonary artery → aorta.

Preductal or Infantile type:

Postductal or Adult type:

Signs and symptoms of coarctation of aorta

Complications of coarctation of aorta

Congenital heart disease associations

• Fetal erythropoiesis occurs in:

Surface anatomy of the heart:

Anatomy of the conduction system

Anatomy of the AV node

Anatomy of the SA node

Biventricular peacemaker of the heart

• UW: coronary sinus:

Blunt aortic injury (traumatic aortic rupture)

Coronary artery anatomy

• Coronary blood flow peaks in early diastole.

• Stroke Volume (SV) = EDV -ESV

1. Catecholamine stimulation via β-1 1. β-1 blockade (↓ cAMP).

To INCREASE Preload To DECREASE Preload

1. Add volume (blood, IVF) 1. Remove volume (bleeding, dehydration)

To INCREASE Afterload To DECREASE Afterload

1. Raise mean blood pressure. 1. Lower the mean blood pressure.

• LV compensates for increased afterload by thickening (hypertrophy) in order to decrease

❖ Venous vasodilators (eg, nitrogycerin) → ↓ preload.

Cardiac output equations

Work of the heart

Cardiovascular Response to Exercise

Resistance and Compliance

Total Peripheral Resistance

• Organ removal “eg, nephrectomy” → ↑ TPR → ↓ CO.

Application of flow equation

Velocity and Area

Flow Properties of Blood Vessels

• Afterload: Increases pressure in left ventricle

Pressure overload Volume overload

▪ Due to increased afterload. ▪ Due to increased preload.

Regulation of blood pressure

Coronary Blood Flow

Pressure-volume Loop & cardiac cycle:

UW: ↑ESV→ more volume remaining in the ventricle after contraction.