Nitrates

Summary
Nitrates are a class of medications that increase the release of nitric oxide (NO) in vascular smooth
muclse cells, leading to smooth muscle relaxation and subsequent vasodilation. Veins are affected
more than arteries, and most therapeutic effects of nitrates result from venous pooling and
subsequently decreased preload. Rapid- and short-acting nitrates are primarily used in the
symptomatic treatment of acute angina pectoris and hypertensive urgency. Side effects may
include headache (nitrate-induced headache), gastroesophageal reflux,
and hypotension with syncope. Prior intake of PDE-5 inhibitors significantly increases the risk
of hypotension.

Agents and dosages

Agents  Formulations Long- Onset of Duration
vs. short- action of action
acting

Nitroglycerin  Oral  Sho  2–5  15–

rt minutes 30
 Subling
minutes
ual

 Transde  Lon  30  8–14

rmal patch g minutes hours

Isosorbide  Subling  Sho  2–5  1–2

dinitrate ual rt minutes hours

 Oral  Lon  1  4-6

g hour hours

Isosorbide  Oral  Lon  30–  6–

mononitrate g 45 24 hours
minutes

Sodium  Intraven  Used primarily for hypertensive

nitroprusside ous crises (see “Indications” below) 

Effects
 Exogenous supply of nitric oxide (NO) through nitrate → activation
of guanylyl cyclase → ↑ cyclic guanosine
monophosphate (cGMP) → activation of protein kinase G
o Increases SERCA activity → ↓ intracellular calcium → ↓ recruitment of
contractile units → vasodilation
 o Increases myosin light chain phosphatase activity →
↓ phosphorylated myosin → smooth muscle relaxation
→ vasodilation
 Peripheral vasodilation
 Decreased preload through venous dilation (venous
pooling) → reduces myocardial wall
tension → improved myocardial perfusion
 Decreased afterload → reduces contraction
effort → ↓ myocardial oxygen demand 
 Dilates veins >>> arteries
 Coronary dilation → improved myocardial perfusion 
 In patients with atherosclerotic CAD, arterioles are
already dilated to maximize cardiac blood flow (due to flow-
limiting stenosis) → difficult to dilate coronary vessels further
→ limited effect of nitrates
 Anginal pain relief: ↓ preload through venous pooling → ↓ heart size
→ ↓ oxygen demand → ↓ pain

Side effects
 Circulatory dysregulation: hypotension, reflex sympathetic activity
→ reflex tachycardia → nitrate syncope
 Nitrate-induced headache: vasodilation of the cerebral arteries
 Gastroesophageal reflux: relaxation of the lower esophageal sphincter
 Development of tolerance 
o Prevention: intermittent therapy with nitrate-free intervals of at
least 8 hours
 Cyanide toxicity after sodium nitroprusside infusion (see cyanide
poisoning)
 Methemoglobinemia
 “Monday disease”: Industrial workers who are exposed to nitrates
during the work week develop a tolerance over the course of the week;
no exposure during weekends leads to loss of tolerance. Reexposure on
Monday causes dizziness and headache.

Indications
 Angina pectoris
o Short-acting nitrates such as sublingual nitroglycerin, isosorbide
dinitrate, or nitroglycerin spray for treatment of acute attacks.
o Long-acting nitrates such as isosorbide mononitrate can be taken
regularly (2–3 times daily) for anginal prophylaxis: unlike some other
nitrates, isosorbide mononitrate does not undergo first-pass
metabolism by the liver and thus has ∼100% bioavailability.
  Hypertensive crisis: short-term reduction of blood pressure
 Hypertensive pulmonary edema
 Chronic heart failure 

Contraindications
 Hypotension
o Risk of life-threatening hypotension if taken within 24 hours of
a PDE-5 inhibitor (e.g., patients with angina pectoris) 
 Stenosis of the left ventricular ejection tract (aortic
stenosis, hypertrophic obstructive cardiomyopathy)
 Myocardial infarction with right ventricular failure
 Increased intracranial pressure
.

Coronary artery disease

Summary
Coronary heart disease (CHD) refers to a mismatch between myocardial oxygen supply and
demand. Atherosclerosis is the most important cause. Atherosclerotic changes in coronary vessel walls lead to
a narrowing of the lumen and prevent vessels from dilating. As a result, an increase in oxygen demand (e.g.,
during physical activity) can no longer be satisfied and/or myocardial perfusion at rest is insufficient. Acute
retrosternal chest pain (angina) is the cardinal symptom of CHD. Other symptoms include dyspnea, dizziness,
anxiety and nausea. If ischemia is severe, myocardial infarction can occur. Coronary heart disease is diagnosed
via a cardiac stress test (possibly provoking symptoms and instrumental findings) and/or coronary
catheterization (e.g., measurement of coronary blood flow). Management of CHD involves primary and
secondary prevention of atherosclerosis (e.g., weight reduction), antianginal treatment (e.g., beta blockers)
and, in some cases, revascularization (e.g., PCTA).

This learning card provides a basic overview of coronary heart disease and stable

angina. Atherosclerosis and acute coronary syndrome (including myocardial infarction) are discussed in
separate learning cards.

Epidemiology
 Lifetime risk of coronary heart disease 
o Age 40: 49% in men and 32% in women
o Age 75: 35% in men and 24% in women
 Cardiovascular disease is the leading cause of death in the US and the world.
References:[1][2][3]

Epidemiological data refers to the US, unless otherwise specified.

FEEDBACK

Etiology
 Risk factors for atherosclerosis

Pathophysiology
 Plaque formation and coronary artery stenosis
 For plaque formation, see pathogenesis of atherosclerosis.
 Stable atherosclerotic plaque → vascular stenosis → increased resistance to
blood flow in the coronary arteries → decreased myocardial blood flow
→ oxygen supply-demand mismatch → myocardial ischemia
 The extent of coronary stenosis determines the severity of the oxygen supply-
demand mismatch and, thus, the severity of myocardial ischemia.
 Severe ischemia results in myocardial infarction (see acute coronary
syndrome for details).
 Coronary flow reserve (CFR): the difference between maximum coronary blood
flow and coronary flow at rest; a measure of the ability of the
coronary capillaries to dilate and increase blood flow to the myocardium.
o In healthy individuals, the CFR can be up to 4 times higher on exertion than
at rest.
o CFR is reduced in individuals with CAD due to vascular stenosis and
reduced vascular compliance.

Myocardial oxygen supply-demand mismatch

 Definition: mismatch between the amount of oxygen the myocardium receives
and the amount it requires
 Factors reducing oxygen supply
o Coronary atherosclerosis 
 and sequelae, including:
 Rupture of an unstable atherosclerotic plaque (most common cause)
 Thrombosis
 Stenosis
o Vasospasms
o ↑ Heart rate 
o Anemia 
 Factors increasing oxygen demand 
o ↑ Heart rate
o ↑ Afterload
o Anemia
An increased heart rate reduces oxygen supply and increases oxygen demand!
Effect of vascular stenosis on resistance to blood flow
 The resistance to blood flow within the coronary arteries is calculated using
the Poiseuille equation: R = 8Lη/(πr ), where R = resistance to flow, L =
4

length of the vessel, η = viscosity of blood, and r = radius of the vessel.

 Provided the length of the vessel and viscosity of blood remain constant, the
degree of resistance can be calculated using the simplified formula: R ≈ 1/r
4

Vascular stenosis increases vascular resistance significantly! For example, a 50% reduction in radius results

in a 16-fold increase in resistance: R ≈ 1/(0.5 x r) = [1/(0.5 x r)]  = (2/r) = 16/r
4  4 4  4

Myocardial ischemia
 Reversible ischemia: Tissue is ischemic but not irreversibly dead and,
therefore, still potentially salvageable.
 o Myocardial stunning: acutely ischemic myocardial segments with transiently
impaired but completely reversible contractility
o Hibernating myocardium: a state in which myocardial tissue has persistently
impaired contractility due to repetitive or persistent ischemia
 Partially or completely reversible when adequate oxygen supply is
restored (e.g., after angioplasty or coronary artery bypass grafting)
 Seen in angina pectoris, left ventricular dysfunction, and/or heart
failure
 Irreversible ischemia: tissue necrosis (myocardial scars)

Coronary steal syndrome

 Definition: a phenomenon of vasodilator-induced alteration of coronary blood
flow in patients with coronary atherosclerosis resulting
in myocardial ischemia and symptoms of angina
 Background
o Long-standing CAD requires maximal coronary arterial dilation distal to
the stenosis to maintain normal myocardial function.
o In CAD, the affected coronary artery is maximally dilated distal to
the stenosis to compensate for the reduced blood flow 
o If a vasodilator (e.g., dipyridamole) is administered, the
subsequent vasodilation of healthy vessels causes these to “steal blood from
the stenotic blood vessels, resulting in poststenotic myocardial ischemia
 Clinical relevance: coronary steal is the underlying mechanism
of pharmacological stress testing
o Administration of vasodilators (e.g., dipyridamole)
→ coronary vasodilation → decreased hydrostatic pressure in the normal
coronary arteries → blood shunting back to well-
perfused myocardium → decreased flow to
the ischemic myocardium → myocardial ischemia downstream to the
pathologically dilated vessels → angina pectoris and/or ECG changes
Coronary steal syndrome should not be confused with coronary-subclavian steal syndrome! (see subclavian
steal syndrome for more information)
Chronic ischemic heart disease
Progressive heart failure that occurs after many years of chronic ischemic damage to the myocardium.

Clinical features
Angina
 Typically retrosternal chest pain or pressure
o Pain can also radiate to left arm, neck, jaw, epigastric region, or back.
o Pain does not depend on body position or respiration
o No chest wall tenderness
o Angina may be absent, particularly in younger patients
o Often gradual progression
o Can also present as gastrointestinal discomfort 
 Dyspnea
 Dizziness, palpitations
 Restlessness, anxiety
  Autonomic symptoms (e.g., diaphoresis, nausea, vomiting, syncope)
Stable angina
 Symptoms are reproducible/predictable
 Complaints often subside within minutes 
 , with rest or after administration of nitroglycerin
 Common triggers
o Mental or physical stress
o Exposure to cold
Unstable angina
 Symptoms are not reproducible/predictable
 Usually occurs at rest or with minimal exertion and is usually not relieved by
rest or nitroglycerin
 Every new-onset angina
 Severe, persistent, and/or worsening angina (crescendo angina)
 Increasing intensity, frequency, or duration in a patient with a known stable
angina
Unstable angina is a form of acute coronary syndrome and may progress to myocardial infarction. Most
patients with CHD first become symptomatic with acute myocardial infarction or sudden cardiac death!

Subtypes and variants

Vasospastic angina 
 Description:
o Angina caused by transient coronary spasms (usually occurring close to
areas of coronary stenosis)
o Unrelated to exertion and may even occur at rest (classically at night)
 Etiology: e.g., cigarette smoking, use
of stimulants (e.g., cocaine, amphetamines) or sumatriptan, alcohol,
stress, hyperventilation, exposure to cold
o There is an association with other disorders involving vasospasms
(e.g., Raynaud phenomenon, migraine headaches)
 Epidemiology: average onset around 50 years
 Diagnostics
o Reversible ST elevation on ECG
o No troponin I or T level elevations on serial measurements
o Coronary spasms on angiography confirm the diagnosis
 Treatment
o Risk factor modification
o Calcium channel blockers 
and nitrates: first-line agent for acute attacks and prophylaxis
o Avoid beta-blockers! 
 Prognosis:
 o The five-year survival rate is > 90% (with treatment).
 Persistence of symptoms is common.

Diagnostics
Patient history and physical exam
 History of recurrent angina episodes
 Signs of atherosclerotic vessel disease (e.g., absent foot pulses, carotid bruit) →
see also physical exam in cardiology

Resting ECG
 Best initial test for both types of angina (and other types of chest pain)
 Usually normal in stable angina
 Treat as unstable angina if abnormalities (of the ST segment or the T wave)
occur during an episode of chest pain

Cardiac stress test

Cardiac stress tests are generally most useful in patients with an intermediate pretest probability of coronary
artery disease.

Choosing the most appropriate provocation  and detection methods

 Provocation
o Able to exercise (and no contraindications for exercise testing): exercise stress
test 
o Unable to exercise (and no contraindications to pharmacologic
testing): pharmacologic stress test
 Detection
o Resting ECG can be interpreted: ECG
o Resting ECG cannot be interpreted: imaging
 Example: In a 75-year-old patient with acute aortic dissection, exercise testing
would be contraindicated. If he also has atrial fibrillation, imaging would be
indicated to monitor the test. Therefore, a pharmacologic stress test with
either echocardiography or scintigraphy would be indicated.
Provocation  methods
Both types of stress test can be used with ECG, echocardiography, and/or myocardial perfusion imaging. 

 Clinical features, blood pressure, and heart rate are evaluated/recorded simultaneously.

 Cardiac exercise stress test

o The patient exercises until the target heart rate is achieved (e.g., on a
treadmill).
 Maximum heart rate = 220 – age (in years)
 Target heart rate = 85% of the maximum heart rate
o Contraindications
 Acute myocardial infarction with elevated troponin levels and/or ST
elevations (in the past 2 days)
 Unstable angina pectoris or ST depressions at rest
 Decompensated heart failure or severe symptomatic stenosis of one
or more heart valves
 Acute endocarditis, myocarditis, or pericarditis
  Hemodynamically significant arrhythmias
 Acute thromboembolic disease
 Acute aortic dissection
 Mental or physical impairment to exercise
 Cardiac pharmacological stress test
o IV administration of
positive inotropic/chronotropic substances (e.g., dobutamine)
or vasodilators (e.g., dipyridamole or adenosine) to simulate the effect of
exercise on the myocardium
o Contraindications
 Adenosine, dipyridamole:
 Active bronchospasm or reactive airway disease
 First-degree heart block
 Low systolic blood pressure (< 90 mm Hg)
 Methylxanthines
 Dobutamine
 Myocardial infarction within the last week
 Unstable angina
 Obstructive cardiomyopathy, aortic stenosis
 Tachyarrhythmias
 Left bundle branch block
 Untreated hypertension
 Thoracic aortic aneurysm
Preparation
 If cardiac stress test is done for primary diagnosis, withhold the following:
o Beta blockers, calcium channel blockers, nitrates (48 hours)
o Methylxanthines (especially if a pharmacological cardiac stress test is
considered): caffeine (12 hours), aminophylline (24 hours), dipyridamole (48
hours)
 If cardiac stress test is done for treatment evaluation, medication can be
continued.
Findings in stress-induced ischemia
 Clinical findings: If one of the following symptoms occurs, the exercise stress
should be stopped.
o New onset/intensification of chest pain
o Severe dyspnea, cyanosis, pallor, ataxia, or altered mental status
o Decrease in systolic BP below the resting BP
o Systolic BP > 250 mm Hg or diastolic BP > 120 mm Hg 
 ECG
o Downsloping or horizontal ST depressions of ≥ 0.1 mV in the limb
leads and ≥ 0.2 mV in the precordial leads 
o ST elevations ≥ 0.1 mV (requires immediate test termination!)
 o Excessive or delayed increase in heart rate 
o New onset ventricular arrhythmia
 Imaging
o The goal is to distinguish between: 
 Irreversible ischemia: necrosis (myocardial scars)
 Reversible ischemia: tissue that is ischemic (but not yet irreversibly
dead) and therefore still potentially salvageable
 Myocardial stunning:
acutely ischemic myocardial segments that demonstrate transiently
impaired contractility that is completely reversible
 Hibernating myocardium: persistently impaired myocardial
contractility that is partially or completely reversible when adequate
oxygen supply is restored (e.g., after angioplasty or CABG)
 Caused by chronically reduced coronary blood
flow
 Seen in angina pectoris, left ventricular
dysfunction, and/or heart failure
o Echocardiography
o Radionuclide myocardial perfusion imaging
Patients with new-onset chest pain, ST segment depression, hypotension or arrhythmias should
undergo cardiac catheterization!

Cardiac catheterization
 Indications
o Persistent symptoms of angina despite appropriate therapy or
o Pathological result of the non-invasive examination or
o Noninvasive procedure with ambiguous results and high clinical suspicion
of CHD
 Gold standard of CHD diagnosis
o Information on several qualities (e.g., coronary blood flow, pressure
within heart chambers, cardiac output, oxygen saturation)
o Direct visualization of coronary arteries (coronary angiography)
o Opportunity for direct therapeutic intervention using percutaneous coronary
intervention (see "Treatment” below)

Additional tests
 Holter monitoring: can detect silent ischemia 
 and arrhythmias and be used to evaluate heart rate variability and
pacemaker/ICD function
 Coronary magnetic resonance imaging (CMRI) or coronary computed
tomography angiography (CCTA) 

Differential diagnoses
 See differential diagnosis of chest pain.
Treatment
Approach
 All patients: risk factor reduction and antiplatelet drugs; see “Prevention”
below
 Mild CHD: pharmacologic therapy
 Moderate CHD: consider coronary angiography and percutaneous transluminal
coronary angioplasty (PTCA)/percutaneous coronary intervention (PCI)
 Severe CHD: coronary angiography and revascularization or coronary artery
bypass grafting

Antianginal treatment
 First-line
o Beta-blockers (except in vasospastic angina): can reduce the frequency of
coronary events 
o Nitrates
 Can prevent exertional angina
 Suitable for relief of acute angina or for long-term treatment
 Second-line
o Calcium channel blockers (CCBs): indicated if there are contraindications
to beta-blockers or in addition to beta-
blockers (if angina or hypertension persist)
o Ranolazine: indicated in stable angina that is refractory to first-
line treatment 
 Two mechanisms of action to reduce myocardial oxygen demand: 1)
inhibit late phase sodium influx into cardiac myocytes → reduced
calcium flux (via sodium-calcium channel pump) → reduced wall stress
and oxygen demand; and 2) decreased rate of fatty acid beta
oxidation (aerobic process) with simultaneous increase
in glycolysis (anaerobic process).
 Combination therapy: indicated if angina persists with monotherapy
o Beta-blocker + nitrates
o Calcium channel blocker (nondihydropyridines) + nitrates
o Beta-blocker + calcium channel blockers (long-acting dihydropyridines, such
as nitrendipine)

Revascularization
 Indications
o In stable angina: activity-limiting symptoms despite optimal medical
treatment, contraindications to medical therapy, stenosis of critical
(e.g., LCA) or multiple coronary arteries
o Acute coronary syndrome
 Techniques
o Percutaneous coronary intervention
o Coronary artery bypass grafting
Prognosis
 Prognostic factors
o Left ventricular function: increased mortality if EF < 50%
o Involvement of left main coronary artery or involvement of more than one
vessel is associated with a worse prognosis.
 Stable angina
o Annual mortality rate: ∼ 5%
o 25% of patients will suffer an acute MI within the first 5 years.
o High-grade stenosis is associated with an unfavorable prognosis.

Prevention
Prevention of atherosclerosis
 Primary and secondary prevention of atherosclerosis

Special considerations in coronary heart disease

 Antiplatelet drugs indicated in all
patients: aspirin or clopidogrel (if aspirin/ASA is contraindicated) → ↓ risk
of infarction, ↓ morbidity
 Treating arterial hypertension
o Reduce blood pressure to < 140/90 mm Hg in cases of low/moderate risk and
to < 130/80 mm Hg in high-risk patients
o Beta-blockers are the first-line therapy for CHD combined with arterial
hypertension. 
o ACE-inhibitors patients post-MI, especially those with left
ventricular systolic dysfunction.
o Calcium channel blockers (for indications, see “Antianginal therapy” above)
  of 6.5–7%
HbA1c

 Risk-adjusted LDL values: see Guidelines for lipid-lowering therapy (ATP III

guidelines) for details 

Aortic valve stenosis

Summary
Aortic stenosis (AS) is a valvular heart disease characterized by narrowing of the aortic valve. As a result, the
outflow of blood from the left ventricle into the aorta is obstructed. This leads to chronic and progressive
excess load on the left ventricle and potentially left ventricular failure. The patient may remain asymptomatic
for long periods of time; for this reason, AS is often detected late, i.e., when it first becomes symptomatic
(dyspnea on exertion, angina pectoris, or syncope). Auscultation reveals a harsh, crescendo-
decrescendo murmur in systole that radiates to the carotids, and pulses are delayed with diminished carotid
upstrokes. Echocardiography is the gold standard for diagnosis. Patients with asymptomatic aortic stenosis are
treated conservatively. Symptomatic patients or those with severe aortic valve stenosis require valve
replacement.

Epidemiology
 Most common valvular heart disease in industrialized countries
 Prevalence:
 o Increases with age 
o May reach up to 12.4% among individuals ≥ 75 years 

Classification
By location of obstruction
 Valvular: most common
 Supravalvular
 Subvalvular

By etiology
 Congenital:
o Bicuspid aortic valve: caused by a fusion of two of the three aortic-valve
leaflets in utero

 Most common congenital heart defect, 3:1 ♂ predominance

 Predisposes the valve to dystrophic calcification and degeneration
 Patients present with symptoms of aortic stenosis earlier than in
regular aortic valve calcification
 Acquired
o Calcific aortic stenosis: most common cause of aortic stenosis
 Characterized by calcification and fibrosis of aortic valve leaflets that
occur at an increasing rate as patients age (prevalence is 65% in those
aged 75–84 years)
 Similar pathophysiology to atherosclerosis (see generic risk factors
for development of arteriosclerosis)
o Rheumatic fever is a rare cause of AS in developed countries, but continues to
remain a significant cause in developing countries. 

Pathophysiology
 Narrowed opening area of the aortic valve during systole → obstruction of
blood flow from left ventricle (LV) → increased LV pressure → left
ventricular concentric hypertrophy →
o Increased LV oxygen demand 
o Impaired ventricular filling during diastole → left heart failure
o Reduced coronary flow reserve 
 Initially, cardiac output (CO) can be maintained. Later, the decreased
distensibility of the left ventricle reduces cardiac output and may then cause
backflow into the pulmonary veins and capillaries →
higher afterload (pulmonic pressure) on the right heart → right heart
failure (see congestive heart failure)

Clinical features
 The disease may remain asymptomatic for years (particularly with mild or
moderate stenosis). 
 Symptoms typically present on exertion, unless AS is severe 
 Dyspnea
 Angina pectoris
 Dizziness and syncope
  Small blood pressure amplitude, decreased pulse pressure 
 Cardiac exam (see cardiovascular examination)
o Weak and delayed distal pulse (pulsus parvus et tardus)
o Palpable systolic thrill over the bifurcation of the carotids and the aorta
o Harsh crescendo-decrescendo (diamond-shaped), late systolic
ejection murmur that radiates bilaterally to the carotids
 Best heard in the 2nd right intercostal space 
 Hand grip decreases the intensity of the murmur. 
 Valsalva and standing from squatting 
decreases or does not change the intensity of the murmur (in contrast
to hypertrophic cardiomyopathy).
o Soft S2 
o S4 is best heard at the apex. 
o Early systolic ejection click 
o Frequently associated with aortic regurgitation (see diagnosis of aortic
regurgitation)
 Additional signs specific to infants: wheezing and difficulty feeding 
SAD (syncope, angina, dyspnea)
Without definite treatment (surgery), more than 50% of the symptomatic patients with severe aortic stenosis
will die within the first 2 years of diagnosis!

Diagnostics
 ECG
o Nonspecific for AS
o Signs of left ventricular hypertrophy (e.g., left axis deviation,
positive Sokolow-Lyon index)
 Chest x-ray 
o Findings of left ventricular hypertrophy, such as left ventricular enlargement
and rounded heart apex, usually only in decompensated aortic stenosis, and
possibly left atrial enlargement as well 
o Narrowing of retrocardiac space (lateral view)
o Calcification of aortic valve: signs of more severe disease
 Echocardiography
o Transthoracic (TTE) or transesophageal (TEE): preferred primary test and
noninvasive gold standard 
 Findings include concentric hypertrophy, narrowing of the opening
of the aortic valve, and increased mean pressure gradient across
the aortic valve.
 Also utilized to determine the severity of stenosis by parameters
such as the mean gradient and cross-sectional area of the opening of the
valve
 Left-heart catheterization 
 o Definitive diagnostic test
o Indication: inconclusive echocardiogram
o Risk of cerebral embolization

Treatment
 Conservative management: regular follow-ups indicated for asymptomatic
patients with mild aortic stenosis
 Surgical (see heart valve prostheses)
o Indications
 Symptomatic patients 
 Asymptomatic patients with severe AS and either significantly ↓ LV
EF or those undergoing cardiac surgery
o Aortic valve replacement (AVR): 3 possible approaches
 Surgical AVR: patients with low surgical risk.
 Transcatheter AVR (TAVR): patients with high surgical risk or
contraindication
 Catheter balloon valvuloplasty: children without AV calcification
The presence of exertional symptoms (dyspnea on exertion, angina pectoris, syncope) is an indication for
surgery!

Prognosis
 Asymptomatic patients: The mortality rate is < 1% in a given year.
 Symptomatic patients: The mortality rate in the first 2 years is > 50%.

Aortic regurgitation
Summary
Aortic regurgitation (AR) is a valvular heart disease characterized by incomplete closure of the aortic
valve that leads to reflux of blood from the aorta into the left ventricle (LV) during diastole. Aortic
regurgitation may be acute (occurring primarily after bacterial endocarditis or aortic dissection) or chronic
(due to congenital bicuspid valve or rheumatic fever) and may be caused by valvular disease or an abnormality
of the aorta. In most cases, acute AR leads to rapid deterioration of LV function with subsequent pulmonary
edema and cardiac decompensation. Frequently, chronic AR may remain compensated for a long period of
time, becoming symptomatic only when left heart failure develops. Auscultation reveals an S3 and a high-
pitched, decrescendo early diastolic murmur. Another characteristic diagnostic finding is widened pulse
pressure. Echocardiography is the most important diagnostic tool, both for confirming the diagnosis and
determining the severity of disease. In asymptomatic patients, conservative treatment consists of symptom
management and physical activity as tolerated. However, symptomatic patients or those with severely reduced
LV function should undergo surgical aortic valve replacement.

Etiology
 Acute AR
 o Infective endocarditis
o Aortic dissection (ascending aorta)
o Chest trauma
 Chronic AR
o Congenital bicuspid valve: most common cause of AR in young adults and
in developed countries
o Rheumatic heart disease: most common cause of AR in developing
countries
o Distortion or dilation of the ascending aorta and aortic root
 Connective tissue disorders (e.g., Marfan syndrome, Ehlers-
Danlos syndrome)
 Tertiary syphilis
 Also see heart valve disease

Pathophysiology
 General
o Regurgitation of blood from the aorta into the left ventricle (LV)
 → Increased systolic blood pressure 
and decreased diastolic pressure 
 → Widened pulse pressure → water hammer pulse (see
“Diagnostics” below)
 Acute AR
o Because LV cannot sufficiently dilate in response to regurgitant blood,
LV end-diastolic pressure increases rapidly → pressure transmits backwards
into pulmonary circulation → pulmonary edema and dyspnea
o Decreased cardiac output if severe → cardiogenic
shock and myocardial ischemia
 Chronic AR
o Initially, a compensatory increase in stroke volume can maintain
adequate cardiac output despite regurgitation (compensated heart failure)
o Over time, increased left ventricular end-diastolic volume → LV enlargement
and eccentric hypertrophy of myocardium → left ventricular systolic
dysfunction → decompensated heart failure

Clinical features
 Acute AR
o Sudden, severe dyspnea
o Rapid cardiac decompensation secondary to heart failure
o Pulmonary edema
o Symptoms related to underlying disease (e.g., fever due to endocarditis, chest
pain due to aortic dissection)
 Chronic AR
o May be asymptomatic for up to decades despite progressive LV dilation
o Palpitations
 o Symptoms of left heart failure
 Exertional dyspnea
 Angina 
 Orthopnea
 Easy fatigability
 Syncope
o Symptoms of high pulse pressure (e.g., head pounding, rhythmic nodding,
or bobbing of the head in synchrony with heartbeats- de Musset sign)

Diagnostics
Physical examination
 For detailed information about the individual tests, see cardiovascular
examination.
 High pulse pressure 
o Water hammer pulse of peripheral arteries characterized by rapid upstroke
and downstroke
o Pulsing of carotid arteries with rapid upstroke and downstroke
o Visible capillary pulse (Quincke sign)
o Nodding of the head with each pulse
 Point of maximal impulse (PMI): displaced inferolaterally, diffuse, and
hyperdynamic 
 Auscultation 
o S3 
o High-pitched, blowing, decrescendo early diastolic murmur 
 AR due to valvular disease: best heard in the left third and
fourth intercostal spaces and along the left sternal border (Erb point)
 AR due to aortic root disease (e.g., aortic dissection): best heard
along the right sternal border
 Worsens with squatting and handgrip 
o Austin Flint murmur 
o In more severe stages, possibly a harsh, crescendo-decrescendo mid-
systolic murmur that resembles the ejection murmur heard in aortic
stenosis 

Confirmatory tests
 Transthoracic echocardiogram (TTE)
o Indicated for suspected AR as well as to monitor confirmed AR to determine
the staging and optimal timing of surgery
o Findings
 Abnormal aortic valve leaflets
 Regurgitant AR jet on Doppler flow tracing
 Increased LV size and volume
 Dilated aorta
 Fluttering of anterior mitral valve leaflet
  Transesophageal echocardiogram (TEE): indicated if suboptimal or
nondiagnostic TTE

Screening tests (optional)
 ECG
o Signs of left ventricular hypertrophy
 Chest x-ray 
o Prominent aortic root/arch 
o Enlarged cardiac silhouette 

Treatment
Conservative
 Indication: asymptomatic patients and symptomatic patients who are not
candidates for surgical treatment
 Treatment of heart failure 
 Physical activity 
, but without excessive straining

Surgical
 Indications [7]

o Symptomatic patients with acute severe AR 

o Asymptomatic patients with:
 Chronic severe AR and EF < 50%
 Left ventricular systolic diameter > 50 mm
 Surgical procedure: aortic valve replacement (occasionally valve
reconstruction is possible) and long-term anticoagulation therapy
for mechanical valve

Prognosis
 Asymptomatic patients with normal EF: progression to symptoms or LV
dysfunction at a rate of < 6% per year
 Asymptomatic patients with decreased EF: progression to symptoms at a rate
of > 25% per year
 Symptomatic patients: mortality rate is > 10% per year

Mitral regurgitation
Summary
Mitral regurgitation (MR) refers to the leakage of blood from the left ventricle to the left
atrium due to incomplete closure of the mitral valve. The most common causes are primary
diseases of the valve (e.g., mitral valve prolapse), although damage may also result secondary to
other heart conditions such as left ventricular dilation and myocardial infarction. Symptoms such
as palpitations or dyspnea appear late in the course of chronic compensated MR in which cardiac
output can still be maintained. In acute or chronic decompensated MR, pulmonary
edema and pulmonary hypertension often cause dyspnea, coughing, jugular venous distention,
and pitting edema. Echocardiography is the most important diagnostic tool and allows for
assessment of severity. It may also be used for preoperative evaluation. Treatment options include
surgical mitral valve repair or replacement and percutaneous reconstruction. Early intervention is
favored in most cases of MR with evidence of left ventricular dysfunction, regardless of symptoms.

Etiology
 Primary MR 
o Degenerative mitral valve disease (mitral valve prolapse, mitral
annular calcification, ruptured chordae tendineae)
o Rheumatic fever
o Infective endocarditis
 Secondary (functional) MR 
o Coronary artery disease, prior myocardial
infarction causing papillary muscle involvement 
o Dilated cardiomyopathy and left-sided heart failure

Pathophysiology
 Acute MR → ↑ LV end-diastolic volume 
 → rapid ↑ LA and pulmonary pressure → pulmonary venous
congestion → pulmonary edema
 Chronic (compensated) MR: progressive dilation of the LV
(via eccentric hypertrophy) 
 → ↑ volume capacity of the LV (preload and afterload return to normal
values) → ↑ end-diastolic volume → maintains ↑ stroke volume
(normal EF)
 Chronic (decompensated) MR: progressive LV
enlargement and myocardial dysfunction → ↓ stroke volume → ↑ end-
systolic and end-diastolic volume → ↑ LV and LA pressure →
pulmonary congestion, possible acute pulmonary edema, pulmonary
hypertension, and right heart strain

Clinical features
 Acute mitral regurgitation
o Symptoms of left-sided heart failure
o Signs and symptoms of pulmonary edema
o Cardiogenic shock
 Chronic mitral regurgitation: late onset of symptoms
o (Exertional) dyspnea, dry cough 
o Palpitations
o Symptoms of left-sided heart failure
Diagnostics
 Auscultation 
o See “Auscultation in valvular defects”
o Quiet first heart sound (S1)
o S3 gallop in advanced stages of disease 
o Holosystolic murmur
 Radiates to the left axilla and heard loudest over the
apex (5  ICS at the left mid-clavicular line)
th

 Intensity increases with increased systemic vascular

resistance (hand grip, squatting)
o Cardiac impulse is often prominent
 ECG
o Left cardiac hypertrophy and P mitrale
o Later, signs of right heart strain with P pulmonale
 Chest X-ray
o Posterior-anterior image
 LV enlargement: laterally displaced left cardiac border 
 LA enlargement: straightening of the left cardiac border
 Signs of pulmonary congestion in late stages of disease (see
“X-ray findings in pulmonary congestion”)
o Lateral image: Narrowing of the retrocardiac space
 Echocardiography: most important diagnostic method for detecting
and assessing valvular abnormalities
o Valve apparatus (e.g., dimensions of valve opening area, calcification,
rupture of the chordae tendineae) and mobility
o LV and LA size and function
 Coronary angiography: prior to surgical intervention

Myocardial infarction must be ruled out in patients presenting with acute MR!

Treatment
 Acute mitral regurgitation
o Hemodynamic stabilization: diuretics, nitrates, antihypertensive
drugs
o Intra-aortic balloon pump if pharmacologic management is
insufficient
o Urgent surgical valve repair or replacement
 Chronic mitral regurgitation
 o Asymptomatic patients
 Without evidence of LV dysfunction (EF > 60%): conservative
management (regular follow-ups, avoidance of physical exertion),
management of underlying and/or secondary diseases
 With evidence of LV dysfunction (EF < 60%): early
surgical valve repair or replacement
o Symptomatic patients
 Without evidence of severe LV dysfunction (EF > 30%):
early valve repair or replacement (mechanical prosthetic
valve or biological prosthetic valve)
 With severe LV dysfunction (EF < 30%): surgical valve
repair or replacement only if the patient is hemodynamically
stable 
;
 Alternatives for severe LV dysfunction:
 Percutaneous reconstruction
 Medical management of heart failure

Complications
 Heart failure, cardiac decompensation, and pulmonary edema
 Atrial fibrillation and arterial emboli
 Endocarditis

Mitral valve stenosis

Summary
Mitral stenosis (MS) is a valvular anomaly of the mitral valve that leads to obstruction of blood
flow into the left ventricle. The most common cause of MS is rheumatic fever. The clinical
manifestations depend on the extent of stenosis: reduced mitral opening leads to progressive
congestion behind the stenotic valve. Initial dilation of the left atrium (complications: atrial
fibrillations, emboli) is followed by progressive congestion of the lungs and subsequent cardiac
asthma (coughing, dyspnea). Acute decompensation can cause pulmonary
edema. Echocardiography is the main diagnostic tool for evaluating the mitral valve apparatus, left
atrial size, and pulmonary pressure. In the event of high grade and/or symptomatic stenosis,
percutaneous valvuloplasty or surgical valve replacement is often required.

Etiology
 Most commonly due to rheumatic fever 
 Autoimmune diseases: systemic lupus erythematosus, rheumatoid
arthritis
 Congenital
  Some conditions may mimic mitral stenosis: bacterial endocarditis of
the mitral valve with large vegetation, left atrial myxoma
 Degenerative aortic stenosis 

Pathophysiology
 Mitral valve stenosis → obstruction of blood flow into the left
ventricle (LV) → limited diastolic filling of the LV (↓ end-diastolic LV
volume) → decreased stroke volume → decreased cardiac
output (forward heart failure)
 Mitral valve stenosis → increase in left atrial pressure → backup of
blood into lungs → increased pulmonary capillary pressure
→ cardiogenic pulmonary edema → pulmonary
hypertension → backward heart failure and right ventricular
hypertrophy

Clinical features
 Initially asymptomatic (onset ∼ 10 years after acute rheumatic carditis)
 Dyspnea (paroxysmal nocturnal dyspnea) and orthopnea, especially
when supine 
 Hemoptysis
 Atrial fibrillation
 Later stages: signs and symptoms of right-sided heart failure

Diagnostics
 Auscultation (see auscultation in valvular defects)
o Diastolic murmur typically heard best at the 5  left intercostal
th

space at the mid-clavicular line (the apex)

 Heard loudest when the patient is lying on his/her left side.
o Loud first heart sound (S ) 1

o Opening snap of the mitral valve after S : A high-frequency, early-to-

2

mid diastolic sound that occurs when leaflet motion suddenly stops

during diastole after the stenosed valve has reached its maximum
opening
 Shorter interval between S  and opening snap indicative of
2

more severe disease, because left atrial pressure is greater than

left ventricular end diastolic pressure (LVEDP)
 Chest x-ray
o Posterior-anterior image
 LA enlargement with prominent left auricle (left atrial
appendage) → straightening of the left cardiac border
  Signs of pulmonary congestion (see X-ray findings in
pulmonary congestion)
o Lateral image
 Dorsal displacement of the esophagus (visible in barium
swallow test)
 Signs of right ventricular hypertrophy
 ECG
o P mitrale
o Atrial fibrillation
o Signs of right ventricular hypertrophy (Sokolow-Lyon index)
 Echocardiography: most important diagnostic method for detecting
and assessing valvular abnormalities
o Abnormal valve mobility
o Subvalvular thickening
o Leaflet thickening
o Calcification
 Coronary angiography may be conducted prior to surgical
interventions to assess the associated risk of coronary artery disease

Treatment
 Conservative treatment
o Treatment of heart failure: only diuretics may be administered!
o Beta blockers or calcium channel blockers: ↓ heart rate and ↓ cardiac
output 
o Endocarditis prophylaxis (see “Infective endocarditis”)
 Interventional
o Indication: high grade and/or symptomatic mitral stenosis
o First-line: percutaneous balloon commissurotomy of the mitral
valve
o Alternatives: open commissurotomy and surgical valve
replacement (mechanical prosthetic valve or biological prosthetic
valve)
ACE inhibitors and other afterload-reducing drugs are contraindicated because they cause dilation
of peripheral blood vessels, which may lead to cardiovascular decompensation!

Complications
 Atrial fibrillation → thromboembolic events
 Progressive congestion of the lungs, pulmonary edema, pulmonary
hypertension
 Congestive heart failure
 Enlarged left atrium (rare) → esophageal compression, recurrent
laryngeal nerve palsy