B4M1C4: Cardiovascular System Flashcards
What are the anatomical valve areas?
● Tricuspid valve
● Mitral valve
● Pulmonary valve
● Aortic valve
What is on the right half of sternum opposite the 4th ICS?
Tricuspid valve
What is on the left half of the sternum opposite 4th LCC (left Costal Cartilage)?
Mitral valve
What is on the Medial end of 3rd LCC (Left Costal Cartilage) and adjoining part of sternum?
Pulmonary valve
What is on the Left half of the sternum opposite the 3rd ICS?
Aortic valve
Where are the different heart sounds are best heard?
○ Mitral area - at and around the cardiac apex (over the apex of the left ventricles)
○ Tricuspid area - at or near the lower left sternal border (over the right ventricle)
○ Pulmonic area - 2nd and 3rd left interspaces close to the sternum (upward along the pulmonary areas)
○ Aortic area - 2nd right interspace (upward along the
aorta).
● It’s a low slightly prolonged “lub”, caused by vibration set up by the sudden closure of the mitral and tricuspid at the start of the ventricular systole.
● Normally heard over the entire precordium
● S1 is usually louder than S2 at the cardiac apex (left 5th ICS near the midclavicular line)
● It is usually fainter than S2 at the base of the heart.
● It marks the beginning of the ventricular systole.
First heart sound (S1)
● It’s a shorter, high-pitched “dup”, caused by vibrations associated with the closure of the aortic and pulmonary valves just after the end of ventricular systole.
● The aortic valve component (A2) precedes the pulmonic component (P2).
● A2 is best heard in the medial end of the 2nd right ICS while P2 is best heard in the medial end of the 2nd left ICS.
● It is usually louder than S1 at the base of the heart.
Second heart sound (S2)
Soft, low-pitched heard about one-third of the way through diastole in many normal young individuals. It coincides with the period of rapid ventricular filling and is probably due to vibrations set up by an in-rush of blood.
Third heart sound (S3)
Sometimes heard immediately before (S1) when atrial pressure is high.
It is due to ventricular filling and is rarely heard in normal adults.
Fourth heart sound (S4)
The atrial pressure changes are transmitted to the great veins, producing three characteristic waves in the record of Jugular pressure:
○ a wave
○ c wave
○ v wave
due to atrial systole
a wave
occurs when the ventricle begins to contract; caused partly by slight backflow of blood into the atria at the onset of ventricular contraction but mainly by bulging of the AV valve backward toward the atria because of increased pressure in the ventricle
c wave
occurs toward the end of ventricular contraction; it results from slow flow of blood into the atria from the veins while the AV valves are closed during ventricular contraction
v wave
What is characterized principally by deforming fibrotic valvular disease, particularly mitral stenosis, of which it is virtually the only cause?
Chronic rheumatic heart disease
What is the most common cause of heart disease in children in developing countries and is the major cause of mortality and morbidity in adults as well?
CHRONIC RHEUMATIC HEART DISEASE
CHRONIC RHEUMATIC HEART DISEASE most commonly affects what gender?
More commonly affects females, sometimes up to twice as frequently as males.
KEY PATHOLOGIC FEATURE OF CHRONIC RHEUMATIC HEART DISEASE
● Organization of the acute inflammation and subsequent deforming fibrosis, particularly the valvular leaflets become thickened and retracted, causing permanent deformity.
● The mitral valve is virtually always deformed.
● The cardinal anatomic changes of the mitral (or tricuspid) valve are leaflet thickening; commissural fusion; and shortening, thickening, and fusion of the tendinous cords.
● Microscopically, there is diffuse fibrosis, and often neovascularization that obliterates the originally layered and avascular leaflet architecture. Aschoff bodies are replaced by fibrosis scars.
Valve lesions and etiologies:
Mitral stenosis
Rheumatic fever
Congenital
Severe mitral annular calcification
SLE, RA
Mitral regurgitation
Acute
Endocarditis
Papillary muscle rupture (post-MI)
Trauma
Chordal rupture/leaflet flail (MVP, IE)
Chronic
Myxomatous (MVP)
Rheumatic fever
Endocarditis (healed)
Mitral annular calcification
Congenital (cleft, AV canal)
HOCM with SAM
Ischemic (LV remodeling)
Dilated cardiomyopathy
Radiation
Aortic stenosis
Congenital (bicuspid, unicuspid)
Degenerative calcification
Rheumatic fever
Radiation
Aortic regurgitation
Valvular
Congenital (bicuspid)
Endocarditis
Rheumatic fever
Myxomatous (prolapse)
Traumatic
Syphilis
Ankylosing spondylitis
Root disease
Aortic dissection
Cystic medial degeneration
Marfan’s syndrome
Bicuspid aortic valve
Nonsyndromic familial aneurysm
Aortitis
Hypertension
Tricuspid stenosis
Rheumatic
Congenital
Tricuspid regurgitation
Primary
Rheumatic
Endocarditis
Myxomatous (TVP)
Carcinoid
Radiation
Congenital (Ebstein’s)
Trauma
Papillary muscle injury (post-MI)
Secondary
RV and tricuspid annular dilatation
Multiple causes of RV enlargement
(e.g., long-standing pulmonary HTN)
Chronic RV apical pacing
Pulmonic stenosis
Valve disease
Congenital
Postvalvotomy
Endocarditis
Annular enlargement
Pulmonary hypertension
Idiopathic dilation
Marfan’s syndrome
Rheumatic fever is the leading cause of this condition.
MITRAL STENOSIS
Other less common etiologies of obstruction to left atrial outflow: congenital mortal valve stenosis, cor triatriatum, mitral annular calcification with extension into the leaflets, systemic lupus erythematosus, rheumatoid arthritis, left atrial myxoma, and infective endocarditis with large vegetations.
Pure or predominant Mitral Stenosis occurs in approximately 40% of all patients with:
rheumatic heart disease and a history of rheumatic fever
In rheumatic MS, the valve leaflets were diffusely thickened by fibrous tissue and/or calcific deposits. The mitral commissures fuse, the chordae tendineae fuse and shorten, the valvular cusps become rigid, and these changes, in turn, lead to narrowing at the apex of the funnel-shaped (“fish-mouth”) valve.
Calcification of the stenotic mitral valve immobilizes the leaflets and narrows the orifice further.
PATHOPHYSIOLOGY OF MITRAL STENOSIS
● In normal adults the mitral valve orifice is 4-6 cm2.
● In the presence of significant obstruction i.e., when the orifice is less than approximately 2 cm2, blood can flow from the LA to the left ventricle (LV) only if propelled by an abnormally elevated left atrioventricular pressure, the hallmark of MS.
● When the mitral valve opening is reduced to 1 cm2, a LA pressure of approximately 25 mmHg is required to maintain a normal cardiac output (CO).
● The elevated pulmonary venous and pulmonary arterial (PA) wedge pressures reduced pulmonary compliance, contributing to exertional dyspnea.
An increase in heart rate shortens diastole proportionately more than systole and diminishes the time available for flow across the mitral valve.
Therefore, at any given level of CO, tachycardia augments the transvalvular gradient and elevates further the LA pressure. The LV diastolic pressure is normal in isolated MS. LV dysfunction, as reflected in reduced LV ejection fraction (EF), occurs in about one-fourth of patients with severe chronic MS. In severe MS and whenever the pulmonary vascular resistance is significantly increased, the pulmonary arterial pressure (PAP) is elevated even when the patient is at rest. Further elevations of LA, pulmonary arterial wedge, and pulmonary arterial pressure occur during exercise.
The hemodynamic response to mitral obstruction ranges from a normal CO and a high left atrioventricular pressure gradient to a markedly reduced CO and low transvalvular pressure gradient. The clinical and hemodynamic features of MS are influenced by the level of pulmonary arterial pressure. Pulmonary hypertension results from:
○ Passive backward transmission of the elevated LA pressure.
○ Pulmonary arteriolar constriction which presumably is triggered by LA and pulmonary venous hypertension (reactive pulmonary hypertension).
○ Interstitial edema in the walls of the small pulmonary vessels.
○ Organic obliterative changes in the pulmonary vascular bed. Severe pulmonary hypertension results in tricuspid regurgitation (TR) and pulmonary incompetence as well as right-sided heart failure.
Summary: MS impedes LV filling, thereby increasing LA pressure. The elevated LA pressure is transmitted back to the lungs and eventually leads to RV failure.
What is the hallmark of Mitral stenosis?
abnormally elevated left atrioventricular pressure
SYMPTOMATOLOGY OF MITRAL STENOSIS
● In temperate climates, the latent period between the initial attack of rheumatic carditis and the development of symptoms is generally about two decades; most patients begin to experience disability in the fourth decade of life.
● Exertional dyspnea, orthopnea, paroxysmal dyspnea and hemoptysis
● Hemoptysis occurs most frequently in patients who have elevated LA pressures without markedly elevated pulmonary vascular resistance.
● Recurrent pulmonary emboli, sometimes with infarction,are an important cause of morbidity and mortality rates late in the course of MS.
PHYSICAL FINDINGS IN MITRAL STENOSIS
Inspection and Palpation
● Malar flush with pinched and blue facies
● Jugular pulse reveals a prominent A wave due to vigorous right atrial systole
● Diastolic thrill at the cardiac apex, particularly with the patient in the left lateral recumbent position.
● Systemic arterial pressure is usually normal or slightly low.
● An RV tap along the left sternal border signifies an enlarged RV.
Auscultation
● Opening snap (OS) of the mitral valve most readily audible in expiration at, or just medial to the cardiac apex; maybe easily heard along the left sternal edge or at the base of the heart.
● Loud S1 (accentuated and snapping) and slightly delayed
● The Pulmonic component of the second heart sound (P2) is often accentuated, and the two components of the second
heart sound (S2) are closely split.
● Pansystolic murmur audible along the left sternal border, usually louder during inspiration and diminishes during forced expiration (Carvallo’s sign).
● Graham Steell Murmur, a high-pitched diastolic, decrescendo-blowing murmur along the left sternal border, results from dilation of the pulmonary valve ring and occurs patients with mitral valve disease and severe pulmonary hypertension.
● Low-pitched, rumbling, diastolic murmur, best heard at the apex,’ with the patient in the left lateral recumbent position; accentuated by mild exercise carried out just before auscultation.
Pansystolic murmur audible along the left sternal border, usually louder during inspiration and diminishes during forced expiration. What is the sign called?
Carvallo’s sign
What is a high-pitched diastolic, decrescendo-blowing murmur along the left sternal border, results from dilation of the pulmonary valve ring and occurs in patients with mitral valve disease and severe pulmonary hypertension?
Graham Steell Murmur
DIFFERENTIAL DIAGNOSIS FOR MITRAL STENOSIS
Mitral Regurgitation
● Prominent diastolic murmur at the apex which commences slightly later than in patients with MS
● Clear-cut evidence of LV enlargement
● Opening snap and increased P2 are absent
● S1 is soft or absent
● Apical pansystolic murmur of at least grade III/VI intensity
● Presence of S3
Primary Pulmonary Hypertension
● Occurs most frequently in young women
● Opening snap and diastolic rumbling murmur are absent
● Pulmonary artery wedge and LA pressures are normal
Atrial Septal Defect
● Absence of LA enlargement and of Kerley B line
● Fixed splitting of S2
● Grade 2 or 3 mid-systolic murmur at the mid to upper left sternal border
Aortic Regurgitation
● Apical mid-diastolic murmur (Austin Flint Murmur) which is not intensified in presystolic and becomes softer with the administration of amyl nitrate.
LABORATORY EXAMINATIONS AND FINDINGS
Electrocardiogram (ECG)
● Sinus rhythm
● Tall and peaked P wave in lead Il and upright in lead V1
● Right atrial enlargement
● Right axis deviation and RV hypertrophy in the presence of severe pulmonary hypertension
● QRS complex is usually normal
Roentgenogram
● Earliest changes are straightening of the left border of the cardiac silhouette, prominence of the main pulmonary arteries, dilatation of the upper lobe pulmonary veins, and backward displacement of the esophagus by an enlarged LA.
● Kerley B lines are fine, dense, opaque, horizontal lines that are most prominent in the lower and midlung fields
Echocardiogram with Doppler (2D Echo w/ Doppler)
● The most sensitive and specific noninvasive methods for diagnosing MS.
● Thickened mitral leaflets with dowing motion in diastole, an elevated mitral gradient and reduced orifice area.
Cardiac Catheterization and Angiocardiography
● Left heart catheterization is useful in clarifying the picture when there is a discrepancy between clinical and echocardiographic findings.
● Helpful in assessing associated lesions such as aortic stenosis and aortic regurgitation.
Coronary Angiography
● Advisable preoperatively to detect patients with critical coronary obstructions that should be bypassed at the time of operation.
Treatment of Mitral Stenosis
Medical Management
● Penicillin prophylaxis of group A β-hemolytic streptococcal infection for secondary prevention of rheumatic fever is important for at risk-patients with rheumatic MS
● For symptomatic patients:
○ Restriction of sodium intake and small doses of oral diuretics
○ Beta blockers, nondihydropyridine calcium channel blockers (DILTIAZEM or VERAPAMIL) and digitalis glycosides are useful in slowing the ventricular rate of patients with AF (atrial fibrillation)
○ Warfarin to an international normalized ratio (INR) of 2 - 3 should be administered indefinitely to patients with MS, who have AF or a history of thromboembolism.
○ If MS is not severe enough to warrant percutaneous commissurotomy, reversion to sinus rhythm pharmacologically or using electrical countershock is indicated.
Surgical Management
● Mitral valvotomy is indicated in symptomatic (New York Heart Association (NYHA) Functional Class ll-IV) patients with isolated MS, whose effective orifice (valve area) is <~1 cm2/m2 body surface area or <1.5 cm3 in normal-sized adults.
● Two techniques:
○ Percutaneous mitral balloon valvotomy (PMBV) is the procedure of choice for patients with relatively pliable leaflets with little or no commissural calcium, subvalvular structure not significantly scarred or thickened, and no left atrial thrombus
○ Surgical valvotomy
● Successful valvotomy is defined by 50% reduction in the mean mitral valve gradient and a doubling of the mitral valve area.
● Valvotomy is not recommended for patients who are entirely asymptomatic and/or who have mild stenosis (mitral valve area>1.5cm2)
● Indications for mitral valve replacement (MVR):
○ MS patients with significant associated MR (mitral regurgitation)
○ Patients whose valve has been severely distorted by previous transcatheter or operative manipulation
○ Patients in whom the surgeon does not find it possible to improve valve function significantly with valvotomy
○ Patients with severe M - i.e., an orifice area ≤ 1cm3 and are in NYHA class II (New York Heart Association), i.e., symptomatic with ordinary activity despite optimal medical therapy.
May result from an abnormality or disease process that affects any one or more of the five functional components of the mitral valve apparatus:
○ Leaflets
○ Annulus
○ Chordae tendineae
○ Papillary muscles
○ Subjacent myocardium
MITRAL REGURGITATION
ETIOLOGY OF MITRAL REGURGITATION
Acute
● Acute myocardial infarction (MI) with papillary muscle rupture
● Blunt chest wall trauma
● Infective endocarditis
● Rupture of chordae tendineae
Chronic Rheumatic Heart Disease
● Rheumatic fever
● Mitral valve prolapse (MVP)
● Extensive mitral annular calcification
● Congenital valve defects (atrioventricular cushion defect and cleft anterior mitral valve leaflet)
● Hypertrophic obstructive cardiomyopathy (HOCM)
● Dilated cardiomyopathy
● Ischemia (ventricular remodeling)
PATHOPHYSIOLOGY OF MITRAL REGURGITATION
● The resistance of LV emptying is reduced.
● As a consequence, the LV is decomposed into the LA during ejection, and with the reduction in LV size, there is a rapid decline in LV tension.
● The initial compensation is more complete LV emptying.
● However, LV volume increases progressively as the severity of the regurgitation increases and as LV function deteriorates. This increase in LV volume is often accompanied by a depressed forward cardiac output (CO).
● The regurgitation volume varies directly with LV systolic pressure and the size of the regurgitation orifice; the latter in turn, is influenced profoundly by the extent of LV dilatation.
● Summary:
○ A portion of LV stroke volume is pumped back into the LA in systole causing increased LA pressure and decreased cardiac output.
SYMPTOMATOLOGY: MITRAL REGURGITATION
● Patients with chronic mild-to-moderate isolated MR are usually asymptomatic.
● Fatigue, exertional dyspnea, and orthopnea are the most prominent complaints in chronic, severe MR.
● Palpitations are common and may signify the onset of AF
● Right-sided heart failure, with painful hepatic congestion, ankle edema, distended neck veins, ascites, and secondary tricuspid regurgitation, occurs in patients who have associated pulmonary vascular disease and marked pulmonary hypertension.
PHYSICAL FINDINGS OF MITRAL REGURGITATION
Palpation
● Arterial pressure is usually normal
● Sharp upstroke of arterial pulse in chronic severe MR
● Jugular venous pulse shows abnormally prominent A wave is patients with sinus rhythm.
● Systolic thrill palpable at the cardiac apex.
● LV is hyperdynamic with a brisk systolic impulse and a palpable rapid-filling wave (S3), and the apex beat is often displaced laterally.
● RV tap and the shock of pulmonary valve closure may be palpable in patients with marked pulmonary hypertension.
Auscultation
● S1 is generally absent, soft, or buried in the holosystolic murmur.
● Wide splitting of the S2 due to premature closure of aortic valve seen in severe MR
● Low-pitched S3 occurring 0.12-0.17 seconds after the aortic valve closure sound.
○ Caused by the sudden tensing of the papillary muscles, chordae tendineae, and valve leaflets.
○ An important auscultatory feature of severe MR
○ Absence of S3 indicates that if MS exists, it may not be severe.
● Systolic murmur of at least grade III / VI intensity
○ Most characteristic auscultatory finding in chronic severe MR.
○ Usually holosystolic, decrescendo
○ Ceases in mid - to- late systole, most prominent at the apex and radiates into the axilla in MR due to papillary muscle dysfunction or mitral valve prolapse.
○ Transmitted to the base of the heart in patients with ruptured chordae tendineae or primary involvement of the posterior mitral leaflet
■ In ruptured chordae tendineae, the systolic murmur may have a cooing or “seagull” quality
■ A flail leaflet may cause a murmur with a musical quality
■ Intensified by isometric exercise (handgrip) but is reduced during the strain phase of Valsalva maneuver.
EXAMINATIONS AND FINDINGS FOR MITRAL REGURGITATION
Electrocardiogram (ECG)
● Sinus rhythm with evidence of LA enlargement
● Atrial Fibrillation in chronic severe M
● RA enlargement may be present when pulmonary hypertension is severe
● No clear-cut ECG evidence of enlargement of either ventricle in many patients.
Roentgenogram
● LA and LV are the dominant chambers
● LA may be massively enlarged and forms the right border of the cardiac silhouette in chronic cases
● Marked calcification of the mitral leaflets in long-standing combined MR and MS.
● Calcification of the mitral annulus.
Echocardiogram
● Color flow Doppler imaging is the most accurate non-invasive technique for the detection and estimation of MR.
● Two-dimensional echocardiography is useful for assessing LV function from end-systolic and end-diastolic volumes and ejection fraction (EF).
○ LA is usually enlarged and/or exhibits increased pulsations
○ LV may be hyperdynamic
TREATMENT OF MITRAL REGURGITATION
Medical Management
● The management of chronic severe MR depends to some degree on its cause.
● Warfarin should be given once AF intervenes with a target INR (international normalized ratio) of 2-3
● Cardioversion should be considered depending on the clinical context and left atrial size
● Asymptomatic patients with severe MR in sinus rhythm with normal LV size and systolic function should avoid isometric forms of exercise
● Diuretics, intravenous vasodilators (particularly Sodium Nitroprusside) and intra aortic balloon counterpulsation for patients with post - MI papillary muscle rupture or other forms of acute severe MR
Surgical Management
● Repair usually consists of valve reconstruction using a variety of valvuloplasty techniques and insertion of an annuloplasty ring.
● Indications of mitral valve repair in chronic, nonischemic, severe MR.
○ Occurrence of symptoms
○ Recent onset of AF and pulmonary hypertension, defined as a PA pressure ≥50mmHg at rest or ≥60
mmHg with exercise
○ Progressive LV dysfunction with LVEF falling below 60% and/or end-diastolic dimension increasing beyond 40mm.
● Repair spares the patient the long-term adverse
consequence of valve replacement, i.e., thromboembolic and hemorrhagic complications in the case of mechanical prostheses and late valve failure necessitating repeat valve replacement in the case of bioprostheses.
● By preserving the integrity of the papillary muscles, subvalvular apparatus, and chordae tendineae, mitral repair, and valvuloplasty maintain LV function to a relatively greater degree.
● Occurs in about 1⁄4 of all patients with chronic valvular heart disease.
● 80% of adult patients with symptomatic valvular AS are male.
AORTIC STENOSIS
AORTIC STENOSIS ETIOLOGY
● Degenerative calcification of the aortic cusps - in adults
● Congenital-bicuspid aortic valve (BAV)
● Chronic- tri-leaflet deterioration, or previous rheumatic
inflammation (rheumatic fever)
PATHOPHYSIOLOGY OF AORTIC STENOSIS
● The obstruction to LV outflow produces a systolic pressure gradient between the LV and aorta.
○ The LV output is maintained by the presence of concentric LV hypertrophy. This serves as a useful compensatory mechanism because it reduces toward normal the systolic stress developed by the myocardium.
● A mean systolic pressure gradient >40 mmHg with a normal CO or an effective aortic valve area <~1 cm2 (or ~<0.6 cm3/m2 body surface area in a normal-sized adult) - i.e., less than approximately 1/3 of the normal orifice area - is generally considered to represent severe obstruction to LV outflow.
● The elevated LV end-diastolic pressure signifies the presence of LV dilation and/or diminished compliance of the hypertrophied LV wall.
○ The CO at rest is within normal limits but fails to rise normally during exercise.
○ Late in the course the CO and LV-aortic pressure gradient decline, and the mean LA, PA, and RV pressures rise.
● The hypertrophied LV muscle mass elevates myocardial oxygen requirement
● Summary: Aortic stenosis produces a pressure overload on the LV due to the greater pressure that must be generated to force blood past the stenotic aortic valve
MORPHOLOGIC FEATURES OF AORTIC STENOSIS
● The morphologic hallmark of nonrheumatic-,-calcific-aortic stenosis is heaped-up calcified masses within the aortic into the sinuses of Valsalva, preventing the opening of the cusps.
○ The calcific deposits distort the cuspal architecture, primarily at the bases.
○ The calcific process begins in the valvular fibrosis, at the points of maximal cusp flexion, and the microscopic layered architecture is largely preserved.
○ In contrast to rheumatic aortic stenosis, commissural fusion is usually absent in degenerative aortic stenosis.
○ The mitral valve is generally normal in patients with calcific aortic stenosis.
● In a congenitally bicuspid aortic valve, the 2 cusps are usually of unequal size, with the larger cusp having a midline raphe, resulting from the incomplete embryologic separation.
○ Valves that become bicuspid owing to an acquired deformity have a conjoined cusp containing the fused commissure that is generally twice the size of the nonconjoined cusp.
○ The raphe that composes the incomplete commissure is frequently a major site of calcific deposits.
AORTIC STENOSIS
● In adults, usually asymptomatic until middle or old age.
● What are the 3 cardinal symptoms?
○ Dyspnea - results primarily from elevation of the pulmonary capillary pressure caused by elevations of LV diastolic pressures 2° to reduced left ventricular compliance and impaired relaxation.
○ Angina pectoris - develops later and reflects an imbalance between the augmented myocardial O2 requirements and reduced O2 availability.
○ Exertional Syncope - may result from a decline in arterial pressure caused by vasodilation in the exercising muscles and inadequate vasoconstriction in nonexercising muscles in the face of a fixed CO or from a sudden fall in CO produced by arrhythmia.
● Late manifestations: marked fatigability, weakness, peripheral cyanosis, orthopnea, paroxysmal nocturnal
PHYSICAL FINDINGS OF AORTIC STENOSIS
Palpation
● Pulsus parvus et tardus (peripheral arterial pulse rises slowly to a delayed peak)
● Thrill or anacrotic “shudder” palpable over the carotid arteries, more commonly the left
● a wave in the jugular venous pulse is accentuated
● Double apical impulse (with palpable S4)- patients in the left lateral recumbent position
Auscultation
● Early systolic ejection sound - audible in children, adolescents, and young adults with congenital BAV disease
● Paradoxical splitting of S2
● S4 audible at the apex - reflects the presence of LV hypertrophy and an elevated LV end-diastolic pressure
● S3 generally occurs late in course, when the LV dilates and its systolic function becomes severely compromised.
● Ejection (mid) systolic murmur that commences shortly after the S1, increases in intensity to reach a peak toward the middle of ejection and ends just before aortic valve closure.
○ It is characteristically low-pitched, rough, and rasping in character, loudest at the base of the heart, most commonly in the second right intercostal space (ICS).
LABORATORY EXAMINATIONS AND FINDINGS FOR AORTIC STENOSIS
Electrocardiogram
● LV hypertrophy is the main finding
● In advanced cases there is ST-segment depression and T-wave inversion (LV “strain”) in standard leads I and a VL and in the left precordial leads.
Chest X-ray
● Dilated proximal ascending aorta - seen along the upper right heart border in front view
● Absence of valvular calcification in adults - suggests that severe AS is not present
● LV enlargement, pulmonary congestion, and enlargement of the LA, PA, and right heart chambers - seen in later stages of the disease as the LV dilates.
Echocardiogram
● Thickening, calcification, and reduced systolic opening of the valve leaflets and LV hypertrophy - key findings.
● Eccentric closure of the aortic valve cusps is characteristic of congenitally bicuspid valves.
● Severe AS is defined by a valve area of <1 cm2, whereas moderate AS is defined by a valve area of 1-1.5 cm2 and mild AS by a valve area of 1.5-2 cm2.
● This procedure is useful for identifying coexisting valvular abnormalities; for differentiating valvular AS from other forms of LV outflow obstruction, and for measurement of the aortic root and proximal ascending aortic dimension.
Catheterization
● Catheterization of the left and right side of the heart is indicated in the following:
○ Patients with multivalvular disease.
○ Young, asymptomatic patients with noncalcific
congenital AS, to define the severity of obstruction to LV outflow.
○ Patients in whom it is suspected that the obstruction to LV outflow may not be at the aortic valve but rather in the sub- or supra-valvular regions.
● Coronary angiography is indicated to detect or exclude CAD in appropriate patients with severe AS who are being considered for surgery.
TREATMENT FOR AORTIC STENOSIS
Medical Management
● Avoid of strenuous physical activity and competitive sports in patients with severe AS (valve area <1 cm2) even in the asymptomatic stage.
● Medications used for the treatment of hypertension or CAD, including beta blockers and ACE inhibitors, are safe for asymptomatic patients with preserved left ventricular systolic function
● NITROGLYCERIN helps relieve angina pectoris in patients with CAD
● The need for endocarditis prophylaxis is restricted to AS patients with a poor history of endocarditis
Surgical Management
1. Aortic Valve Replacement (AVR):
● Indications for atrial valve replacement (AVR):
○ Patients with severe AS (valve area <1cm² or 0.6 cm²/m² body surface area) who are asymptomatic.
○ Those who exhibit LV dysfunction (Ejection fraction (EF) <50%)
○ Those with BAV disease
○ AN aneurysmal or expanding aortic root
(maximal dimension >4.5 cm or annual increase
in size >0.5 cm/year even if asymptomatic.
● Relative indications for AVR:
○ Abnormal response to treadmill exercise
○ Rapid progression of AS, especially when urgent
access to medical care might be compromised.
○ Very severe AS as defined by a valve area <0.6
cm2
○ Severe LV hypertrophy suggested by a wall
thickness of >15 mm
● Operation should be carried out within 3 -4 months of symptom onset and before frank LV failure develops.
● Age alone is not a contraindication to AVR for AS. The mortality rate depends to a substantial extent on the patient’s preoperative clinical and hemodynamic state.
-
Percutaneous Balloon Aortic Valvuloplasty
● Referable to operation in children and young adults with congenital, noncalcific AS.
● Not commonly used in adults with severe calcific AS because of a very high restenosis rate (80% within 1 year) and the risk of procedural complications. -
Percutaneous Aortic Valve Replacement
● Transcatheter aortic valve implantatión (TAVI) for high-risk adult patients worldwide using one or two available systems, a balloon-expandable valve and a self-expanding valve, both of which incorporate a pericardial prosthesis.
● 3⁄4 of patients with pure or predominant valvular AR are males.
● Females predominate among patients with AR who have associated mitral valve disease.
AORTIC REGURGITATION (AR)
ETIOLOGY: AORTIC REGURGITATION (AR)
Primary Valve Disease
● Rheumatic disease - results in thickening, deformity, and shortening of the individual aortic valve cusps, changes that prevent their proper opening during systole and closure during diastole.
● Congenital BAV disease
● Myxomatous degeneration (prolapsed of an aortic cusp)
● Infective endocarditis
● Syphilis
● Ankylosing spondylitis
● Traumatic rupture or avulsion of the aortic valve - represent the most frequent serious lesion in patients surviving non- penetrating cardiac injuries.
Primary Aortic Root Disease
● Cystic medial degeneration of the ascending aorta associated with Marfan’s syndrome
● Idiopathic dilatation of the aorta
● Annuloaortic ectasia
● Osteogenesis imperfecta
● Severe hypertension
● Syphilitic aortitis
PATHOPHYSIOLOGY: AR
● The total stroke volume ejected by the LV (i.e the sum of the effective forward stroke volume and the volume of the blood that regurgitates backs into the LV) is increased.
● The entire LV stroke volume is ejected into a high-pressure zone, the aorta.
● An increase in the LV end-diastolic volume (increased preload) constitutes the major hemodynamic compensation for aortic regurgitation (AR).
● The dilatation of the LV allows this chamber to eject a larger stroke volume without requiring any increase in the relative shortening of each myofibril.
● As LV function deteriorates, the end-diastolic volume rises, and the forward stroke volume and ejection fraction (EF) decline.
● The reverse pressure gradient from the aorta to LV, which is responsible for the aortic regurgitation, falls progressively during diastole.
● Summary: A portion of the LV stroke volume ejected during systole regurgitates back into the LV during diastole resulting in a volume-overloaded LV.
SYMPTOMATOLOGY OF AR
● Patients may remain relatively asymptomatic for as long as 10-15 years
● Uncomfortable awareness of the heartbeat, especially on lying down, maybe an early complaint.
● Sinus tachycardia during exertion or with emotion, or premature ventricular contractions may produce particularly uncomfortable palpitations as well as head pounding.
● These complaints may persist for many years before the development of exertional dyspnea, usually the first symptom of diminished cardiac reserve.
● Dyspnea is followed by orthopnea, paroxysmal nocturnal dyspnea, and excessive diaphoresis.
● Anginal chest pain even in the absence of CAD may occur in patients with severe AR, even in young patients. It may develop at rest as well as during exertion.
● Nocturnal angina may be a troublesome symptom, and it may be accompanied by marked diaphoresis. Anginal episodes can be prolonged and often do not respond satisfactorily to sublingual nitroglycerin
● Systemic fluid accumulation, including congestive hepatomegaly and ankle edema, may develop late in the course of the disease.
PHYSICAL FINDINGS
● Jarring of the entire body and bobbing motion of the head with each systole.
● Abrupt distention and collapse of the larger arteries.
● Characteristic findings of chronic severe aortic
regurgitation:
○ Rapidly rising: “water-hammer” pulse, which collapse suddenly as arterial pressure falls rapidly during late systole and diastole (CORRIGAN’s PULSE)
○ Capillary pulsations
○ Alternate flushing and paling of the skin at the root of the nail while pressure is applied to the tip of the nail (QUINCKE’S PULSE)
● Light compression of the femoral artery with a
stethoscope with produce the following:
○ Booming, “pistol-shot” sound (Traube’s sign)
○ To-and-fro murmur (Duroziez’s sign)
● Systolic expansion and diastolic retraction of the apex are prominent
● Diastolic thrill is palpable along the left stemal border
● Prominent systolic thrill palpable in the jugular notch and transmitted upward along the carotid arteries.
● Systolic ejection sounds are frequently audible in patients with BAV disease
● High-pitched, blowing, decrescendo diastolic murmur best heard in the 3rd intercostal space along the left sternal border.
○ If AR is caused by primary valvular disease, this murmur is usually louder along the left sternal border.
○ If AR is caused by aneurysmal dilatation of the aortic root, this murmur is heard best along the right sternal border.
● “Cooing” or musical diastolic murmurs suggest the eversion of an aortic cusp vibrating in the regurgitant stream.
● Mid-systolic ejection murmur heard best at the base of the heart and transmitted along the carotid arteries
● Soft, low-pitched, rumbling mid- to - late diastolic murmur (Austin Flint Murmur) which is probably due to diastolic displacement of the anterior leaflet of the mitral valve by the AR stream.
LABORATORY EXAMINATIONS AND FINDINGS
Electrocardiogram
● No electrocardiographic abnormalities in mild AR
● ST-segment depression and T-wave inversions in leads l, a VL, V5, and V6 (“LV strain”)
● LV hypertrophy in severe, chronic AR + above findings
● Left axis deviation and/or QRS prolongation signify a poor prognosis.
Roentgenogram
● Apex is displaced downward and to the left in the frontal projection, and the cardiac shadow extends below the left diaphragm in severe chronic AR
● If AR is due to primary valvular disease, the ascending aorta and aortic knob are moderately dilated.
● If AR is caused by primary disease of the aortic root, aneurysmal dilatation of the aorta is noted.
Echocardiogram
● A rapid, high-frequency fluttering of the anterior mitral leaflet produced by the impact of the regurgitant jet is a characteristic finding.
Angiography
● Coronary angiography is performed routinely in appropriate patients before surgery.
Medical Management
● For patients with severe AR:
○ Intravenous diuretics and vasodilators (such as Sodium Nitroprusside)
○ Intraaortic balloon counterpulsation is contraindicated
○ Beta blockers are best avoided so as not to reduce the CO further or slow the heart rate
○ Surgery is the treatment of choice and is usually
necessary within 24 hours of diagnosis.
● For patients with chronic aortic regurgitation:
○ Diuretics for the early symptoms of dyspnea and effort intolerance
○ Can also give vasodilators (ACE inhibitors,
dihydropyridine calcium channel blockers, or
hydralazine)
○ Full course of penicillin therapy for patients with syphilitic aortitis
Surgical Management
● Two points to consider in the advisability and proper timing of surgical treatment:
○ Patients with chronic severe AR usually do not
become symptomatic until after the development of myocardial dysfunction
○ When delayed too long (defined as > 1 year from onset of symptoms or LV dysfunction), surgical treatment often does not restore normal LV function.
● For chronic severe AR, surgery should be performed after the onset of LV dysfunction but before the development of severe symptoms.
● Aortic valve replacement (AVR) is indicated for severe AR in symptomatic patients irrespective of LV function. In general, the operation should be carried out in asymptomatic patients with progressive LV dysfunction defined by an LVEF <50%, an LV end-systolic dimension >55 mm or end-systolic volume >55mL/m2, or an LV diastolic dimension >75mm.
● Patients with acute severe AR require prompt surgical treatment, which may be lifesaving.
● Patients with rheumatic AR-aortic valve replacement with a suitable mechanical or tissue prosthesis
● If AR is due to aneurysmal dilatation of the root or proximal ascending aorta- narrowing the annulus or excising a portion of the aortic root without valve replacement.
● More common in tropical and subtropical climates, especially on the Indian subcontinent, and in Latin America.
● Generally rheumatic in origin.
● More common in women than in men.
● Usually associated with mitral stenosis.
TRICUSPID STENOSIS (TS)
TRICUSPID STENOSIS
PATHOPHYSIOLOGY
● Presence of a diastolic pressure gradient between the right atrium and right ventricle. This is augmented when the transvalvular blood flow increases during inspiration and declines during expiration.
● A mean diastolic pressure gradient of 4mmHg is usually sufficient to elevate the mean right atrial pressure to levels that result in systemic venous congestion associated with hepatomegaly, and ascites edema.
● The right atrial wave may be extremely tall and may even approach the level of the right ventricular systolic pressure with a prolonged descent because of slow right ventricular filling.
● The CO at rest is usually depressed and fails to rise during exercise.
● The low CO is responsible for the normal or only slightly elevated LA, PA, and RV systolic pressures despite the presence of mitral stenosis.
● Patients with TS can mask the hemodynamic and clinical features of any associated MS.
SYMPTOMATOLOGY
● Initially have symptoms of pulmonary congestion and fatigue
● Relatively little dyspnea for the degree of hepatomegaly, ascites, and edema that they have - characteristic in patients with severe TS
● Fatigue secondary to a low CO and discomfort due to refractory edema, ascites, and marked hepatomegaly - common in patients with TS and TR
PHYSICAL FINDINGS
● Severe TS is associated with marked hepatic congestion, resulting in cirrhosis, jaundice, serious malnutrition, anasarca, and ascites
● Congestive hepatomegaly and splenomegaly
● Jugular veins are distended
● Giant a wave and prominent presystolic pulsation of the enlarged liver in patients with sinus rhythm
● The v waves are less conspicuous and there is a slow y descent
● Typical diastolic murmur along the lower left sternal border mimics mitral stenosis.
● Tricuspid murmur is heard best along the left lower sternal margin and over the xiphoid process and is most prominent during presystole in patients with sinus rhythm.
○ The murmur is augmented during inspiration and is reduced during expiration and particularly during the strain of Valsalva
LABORATORY EXAMINATIONS AND FINDINGS
Electrocardiogram
● Tall, peaked P waves in lead ll
● Prominent, upright P waves in lead V1
● The absence of ECG evidence of right ventricular
hypertrophy (RVH) in a patient with right-sided heart failure who is believed tò have MS should suggest associated tricuspid valve disease
Roentgenogram
● Prominence of the right atrium and superior vena cava without much enlargement of the pulmonary artery
Echocardiogram
● Thickened tricuspid valve and domes in diastole
● Transthoracic echocardiography (TTE) provides additional information regarding mitral valve structure and function, LV and RV size and function, and PA pressure.
TREATMENT
Medical Management
● Intensive salt restriction bed rest, and diuretic therapy during the preoperative period for patients that exhibit marked venous congestion
Surgical Management
● Surgical repair should be carried out preferably at the time of surgical mitral valvotomy or MVR in patients with moderate or severe TS who have mean diastolic pressure gradients exceeding ~4mmHg and tricuspid orifice areas <1.5-2 cm2.
● Prosthetic valve replacement preferably a large bioprosthetic valve if repair cannot be accomplished
Most commonly it is secondary to marked dilation of the tricuspid annulus from RV enlargement due to PA hypertension
TRICUSPID REGURGITATION (TR)
TRICUSPID REGURGITATION (TR)
ETIOLOGY
Primary
● Rheumatic fever
● Infective endocarditis
● Congenital heart disease (Ebstein’s)
● Tricuspid valve prolapsed (TVP)
● Carcinoid heart disease
● Trauma
● Infarction of RV papillary muscles
● Radiation
Secondary
● RV (right ventricular) and tricuspid annular dilatation.
● Multiple causes of RV enlargement (long- standing pulmonary hypertension)
● Chronic RV apical pacing
PHYSICAL FINDINGS
● Distended neck veins with prominent v waves and rapid y descents
● Marked hepatomegaly, systolic pulsations of the liver, positive hepato-jugular reflex
● Ascites
● Pleural effusion
● Edema
● Prominent right ventricular pulsation along the left parasternal region
● Blowing holosystolic murmur along the lower left sternal margin intensified during inspiration and reduced during expiration or the strain of the Valsalva maneuver
LABORATORY EXAMINATIONS AND FINDINGS
Electrocardiogram
● Shows changes characteristic of the lesion responsible for the enlargement of the right ventricle
Roentgenogram
● Enlargement of both right atrium and right ventricle
Echocardiogram
● Right ventricular dilatation and prolapsing, flail, scarred or displaced tricuspid leaflets
TREATMENT
● Isolated TR, in the absence of pulmonary hypertension, is usually well tolerated and does not require an operation.
● If surgery is required - tricuspid annuloplasty (with insertion of a ring), open tricuspid valve repair, or tricuspid valve replacement.
● Most commonly acquired abnormality affecting the pulmonic valve.
● 2° to dilatation of the pulmonic valve ring due to severe pulmonary arterial hypertension.
PULMONIC REGURGITATION
PULMONIC REGURGITATION ETIOLOGY
Valve Disease
● Congenital
● Postvalvotomy
● Endocarditis
Annular enlargement
● Pulmonary hypertension
● Idiopathic dilation
● Marfan’s syndrome
● Produces the Graham Steell murmur, a high-pitched, decrescendo, diastolic blowing murmur along the left sternal border, which is difficult to differentiate from the murmur produced by aortic regurgitation.
● Percutaneous pulmonic valve replacement in patients with severe PR
PULMONIC STENOSIS ETIOLOGY
● Congenital
● Carcinoid syndrome
VALVULAR HEART DISEASE MANAGEMENT
MEDICAL MANAGEMENT
Non-Pharmacologic measures specifically in pregnancy🤰
● Mitral stenosis is most likely to cause death during pregnancy. Careful control of heart rate, especially during labor and delivery, minimizes the impact of tachycardia and reduced ventricular filling times on cardiac function. Balloon valvulotomy can be carried out during pregnancy.
● Mitral regurgitation and aortic regurgitation and stenosis are generally well tolerated during pregnancy. In the most severe cases of aortic stenosis, limitation of activity or balloon valvuloplasty may be indicated
Medical therapy in VHD
Page 10
● It is a glucosaminoglycan, occurs intracellularly in tissues that contain mast cells. It appears to be required for the storage of histamine and certain proteases within mast cell secretory glands.
● Prepared commercially from porcine intestinal mucosa or bovine lung with an average molecular weight of 15,000-20,000 daltons.
● Low-molecular-weight (LMW) fractions of heparin have molecular weights of 1,000-10,000 daltons.
Heparin
MOA of Heparin
● Regular heparin binds and activates endogenous antithrombin (antithrombin III) which inhibits activated coagulation factors of the intrinsic and common pathways, including thrombin (activated factorII) Xa and IXa.
○ Heparin increased the rate of thrombin antithrombin reaction at least 1000-fold by serving as a catalytic template to which both the inhibitor and the protease bind.
○ The binding site for antithrombin on heparin is a specific pentasaccharide sequence that contains a 3-O-sulfated glucosamine residue.
● Low-molecular-weight heparin like regular heparin, binds antithrombin III(ATIII), and this complex has the same inhibitory effect on factor X as the regular heparin-ATIII complex but has a smaller effect on thrombin.
Pharmacologic E ffects of Heparin
● Anticoagulant effect ± disappears within hours of discontinuation of the drug
● Interfere with platelet aggregation ± prolongs bleeding time
● “Clears” lipemic plasma by causing the release of
lipoprotein lipase in the circulation
● Inhibits growth of a variety of cultured cells, including endothelial cells, vascular smooth muscle cells, and renal mesangial cells.
Pharmacokinetics of Heparin
● Not absorbed through the GI mucosa and is given parenterally.
● Administration is by continuous IV infusion or subcutaneous injection.
● Onset of action is immediate when given intravenously but delayed 1-2 hours when given subcutaneously.
● More uniform absorption for low-molecular-weight heparin
● Displays dose-dependent half-life kinetics, although the
half-life may be prolonged in cirrhotic patients and patients with renal dysfunction.
● Low-molecular-weight heparin has longer biological half-lives.
Heparin: Administration and Monitoring
● Full-dose heparin therapy is administered by continuous IV infusion.
● Very high doses are required to prevent coagulation during cardiopulmonary bypass.
● Subcutaneous administration can be used for the long-term management of patients in whom warfarin is contraindicated (e.g., during pregnancy)
○ Heparin does not cross the placenta and has not been associated with fetal malformation - the drug of choice for anticoagulation during pregnancy.
● Therapy routinely is monitored by the APTT.
○ The therapeutic range for standard heparin is
considered to be that which is equivalent to a plasma heparin level 0.3- 0.7 U/ml determined with an anti-factor Xa assay.
○ A clotting time of 1.8-2.5 times the normal mean an APTT value is generally assumed to be therapeutic.
○ APTT should be measured and the infusion rate adjusted every 6 hours.
The dose of heparin required to produce a therapeutic activated partial thromboplastin time (APTT) is variable due to differences in the concentration of heparin-binding proteins in plasma, such as histidine-rich glycoprotein, vitronectin, and platelet factor 4; these proteins competitively inhibit binding of heparin to antithrombin.
Heparin Resistance
Clinical Use of Heparin
● Venous thrombosis and pulmonary embolism
● Initial management of patients with unstable angina or acute myocardial infarction
● During and after coronary angioplasty or stent replacement
● During surgery requiring cardiopulmonary bypass
● Drug of choice for anticoagulation during pregnancy
● LMW heparin is effective in the treatment of venous thrombosis, pulmonary embolism, and unstable angina.
● Advantages of LMW heparin over regular heparin:
○ More predictable pharmacokinetic profile, which allows weight-adjusted subcutaneous administration without laboratory monitoring.
○ Lower incidence of heparin-induced thrombocytopenia
○ Lower risks of bleeding and osteopenia
● LMW heparin preparations: Enoxaparin, Dalteparin, Ardeparin, Nadroparin, Reviparin, Tinzaparin
What is the primary untoward effect of heparin?
Bleeding
Toxicities of Heparin
● Bleeding - primary untoward effect
○ Antidote - Protamine sulfate
■ A mixture of basic polypeptide isolated from salmon sperm
■ Binds tightly to heparin and thereby neutralizes it anticoagulant effect
■ Also interacts with platelets, fibrinogen, and other plasma proteins and may cause an anticoagulant effect of its own.
■ To neutralize the heparin present in the plasma, approximately 1mg of Protamine for every 100 of heparin remaining in the patient is given intravenously at a slow rate (up to 50mg over 10 minutes)
● Heparin-induced thrombocytopenia (platelet count <150,000 μl or a 50% decrease from the pretreatment value)
○ Lower incidence with LMW heparin
○ Heparin should be discontinued immediately if
unexplained thrombocytopenia occur 5 or more days after beginning heparin therapy.
○ May result from the development of IgG antibodies against complexes of heparin with platelet factor 4 or from heparin-induced platelet aggregation
○ Diagnosis can be confirmed by a heparin-dependent platelet activation assay or an assay for antibodies that react with heparin-platelet factor 4 complexes
● Abnormalities of hepatic function test
○ Mild elevation of hepatic transaminases in plasma
● Osteoporosis resulting in spontaneous vertebra fracture
● Inhibit the synthesis of aldosterone by adrenal glands
Contraindications of Heparin
● Patients who are hypersensitive to the drug
● Bacterial endocarditis
● Active tuberculosis
● Actively bleeding
● Recent head trauma
● Neurosurgery
● Recent major surgery
OTHER PARENTERAL ANTICOAGULANTS
DANAPAROID
LEPIRUDIN
● A mixture of nonheparin glucosaminoglycans isolated from porcine intestinal mucosa (84% heparin sulfate, 12% dermatan sulfate, 4% chondroitin sulfate)
● An effective anticoagulant for patients with heparin-induced thrombocytopenia.
● Mainly promotes inhibition of factor Xa by antithrombin, but it does not prolong prothrombin time (PT) or activate partial thromboplastin time (APTT)
● Half-life is about 24 hours.
● Patients with renal failure may require monitoring with an anti-factor Xa assay because of prolonged half-life.
● No antidote available.
DANAPAROID
● A recombinant derivative of hirudin, a direct thrombin inhibitor present in the salivary glands of the medicinal leech.
● is a 65-amino acid polypeptide that binds tightly to both the catalytic site and the extended substrate recognition site (exosite I) of thrombin.
● Administered intravenously, excreted by the kidneys, and has a half-life of about 1.3 hours.
● Daily monitoring of the APTT is recommended.
● No antidote for overdosage
● For treatment of patients with heparin-induced thrombocytopenia
LEPIRUDIN
Heparin’s Properties:
Structure: Large polymers, acid
Route of Administration: Parenteral
Site of Action: Blood
Onset of Action: Rapid (seconds)
**Mechanism of Action **: Activates antithrombin III
Monitoring: aPTT for regular heparin but not LMW heparins
Antidote: Protamine (for regular heparin but not LMW heparins)
Use: Mostly acute, over days
Use in Pregnancy: Yes
Properties of Warfarin:
Structure: Small lipid-soluble molecule
Route of Administration: Oral
Site of Action: Liver
Onset of Action: Slow, limited by half-lives of factors being replaced
**Mechanism of Action **: Impairs synthesis of factors II, VII, IX, X
Monitoring: PT
Antidote: Vitamin K, plasma
Use: Chronic, over weeks to months
Use in Pregnancy: NO
ORAL ANTICOAGULANTS
Mechanism of Action
● Interfere with the normal post translational modification of clotting factors in the liver, a process that depends on Vitamin K
○ The vitamin K - dependent factors include II (Thrombin), VII, IX and X.
Coumarin Anticoagulants (warfarin)
● Bioavailability is nearly complete when administered orally, intramuscularly, intravenously or rectally.
○ IM injection is not recommended because of the risk of hematoma formation.
● Food in the GIT can decrease the rate of absorption
● Almost completely (99%) bound to plasma proteins, principally albumin
● Not found in milk.
● Half-life ranges from 25-60 hours, with a mean of about 40 hours.
● Duration of action is 2-5 days.
● Causes of resistance to warfarin.
○ Excessive vitamin K intake from the diet or parenteral supplementation
○ Noncompliance
○ Laboratory error
● Cytochrome P450 CYP2C9 is the major enzyme responsible for converting S-warfarin to its inactive metabolite.
● Toxicity
○ Bleeding - major toxic effect
■ The risk of bleeding increases with the intensity and duration of anticoagulant therapy, the use of other medications that interfere with hemostasis, and the presence of a potential anatomical source of bleeding.
○ Birth defects and abortion when administered during pregnancy
■ Ingestion during the first trimester will produce a syndrome characterized by nasal hypoplasia and stippled epiphyseal calcifications that resemble chondrodysplasia punctata.
■ Should not be used during pregnancy
○ Coumarin - induced skin necrosis
○ The original anticoagulant isolated and the first used clinically
○ Now seldom used because it is absorbed slowly and erratically, and frequently causes GI side effects.
○ Onset of action is 1-5 days and its effect lasts 2-10 days after withdrawal.
Dicumarol
○ ___________ has a longer plasma half-life (5 dyas) than warfarin, somewhat slower onset of action and a longer duration of action (7-14 days).
○ ___________ has a shorter half-life (10-24 hours), a more rapid effect on the prothrombin time (PT), and a shorter duration of action (2 days)
○ Phenprocoumon has a longer plasma half-life (5 dyas) than warfarin, somewhat slower onset of action and a longer duration of action (7-14 days).
○ Acenocoumarol has a shorter half-life (10-24 hours), a more rapid effect on the prothrombin time (PT), and a shorter duration of action (2 days)
● Indandione Derivatives
Anisindione
Phenindione
What is similar to warfarin in its kinetics of action but offers no clear advantages and may cause higher frequency of untoward effects?
Anisindione
What is no longer recommended for use, and serious hypersensitivity reaction can occur within a few weeks of starting therapy?
Phenindione
Rodenticides:
○ Bromadiolone
○ Brodifacoum
○ Diphenadione
○ Chlorophacinone
○ PIndone
■ Long-acting agents (Prolongation of PT may persist for weeks)
■ Agents of accidental or intentional poisoning.
Clinical Use and Monitoring of Oral Anticoagulants
● To prevent the progression or recurrence of acute deep vein thrombosis or pulmonary embolism following an initial course of heparin.
● Preventing venous thromboembolism in patient undergoing orthopedic or gynecological surgery and systemic embolization in patients with acute MI, prosthetic heart valves; or chronic atrial fibrillation
○ Prior to initiation of therapy, laboratory tests are used to uncover hemostatic defects that might make the use of oral anticoagulants more dangerous.
■ The INR (International Normalized Ratio) calculated from the patient’s PT is used to monitor efficacy and compliance.
■ The PT is prolonged when the functional levels of fibrinogen, factor V, or the vitamin K - dependent factors II, VII, or X are decreased.
Table on page 12. Drug interactions with oral anticoagulants
Differential Diagnosis of Valvular Heart Disease on pages 13-14
