Infective Endocarditis

Practice Essentials

Infective endocarditis (IE) is defined as an infection of the endocardial surface of the heart, which may include one or more heart valves, the mural endocardium, or a septal defect. Its intracardiac effects include severe valvular insufficiency, which may lead to intractable congestive heart failure and myocardial abscesses. If left untreated, IE is generally fatal.

Essential update: Ceftriaxone an alternative treatment for infective endocarditis

In a recent study, the combination of ampicillin and ceftriaxone was shown to be as effective as the combination of ampicillin and gentamicin for treating Enterococcus faecalis infective endocarditis. In this observational study, mortality rates did not differ significantly between the 2 treatments either during antimicrobial therapy or at 3-month follow-up. There were also no significant differences in treatment failures resulting in a change of antimicrobials or in disease relapses.[1, 2]

According to study findings, the need to interrupt antibiotic treatment as a result of adverse events occurred significantly more often in patients treated with the ampicillin/gentamicin combination, primarily because of newly developed renal failure.[1, 2]

Signs and symptoms

Fever, possibly low-grade and intermittent, is present in 90% of patients with IE. Heart murmurs are heard in approximately 85% of patients.

One or more classic signs of IE are found in as many as 50% of patients. They include the following:

Petechiae: Common, but nonspecific, findingSubungual (splinter) hemorrhages: Dark-red, linear lesions in the nail bedsOsler nodes: Tender subcutaneous nodules usually found on the distal pads of the digitsJaneway lesions: Nontender maculae on the palms and solesRoth spots: Retinal hemorrhages with small, clear centers; rare

Signs of neurologic disease, which occur in as many as 40% of patients, include the following[3] :

Embolic stroke with focal neurologic deficits: The most common neurologic signIntracerebral hemorrhageMultiple microabscesses

Other signs of IE include the following:

SplenomegalyStiff neckDeliriumParalysis, hemiparesis, aphasiaConjunctival hemorrhagePallorGallopsRalesCardiac arrhythmiaPericardial rubPleural friction rub

Subacute native valve endocarditis

The symptoms of early subacute native valve endocarditis (NVE) are usually subtle and nonspecific; they include the following:

Low-grade fever: Absent in 3-15% of patientsAnorexiaWeight lossInfluenza-like syndromesPolymyalgia-like syndromesPleuritic painSyndromes similar to rheumatic fever, such as fever, dulled sensorium (as in typhoid), headachesAbdominal symptoms, such as right upper quadrant pain, vomiting, postprandial distress, appendicitis-like symptoms

See Clinical Presentation for more detail.

Diagnosis

The Duke diagnostic criteria, developed by Durack and colleagues, are generally used to make a definitive diagnosis of IE. The criteria combine the clinical, microbiologic, pathologic, and echocardiographic characteristics of a specific case[4] :

Major blood culture criteria for IE include the following:

Two blood cultures positive for organisms typically found in patients with IEBlood cultures persistently positive for one of these organisms, from cultures drawn more than 12 hours apartThree or more separate blood cultures drawn at least 1 hour apart

Major echocardiographic criteria include the following:

Echocardiogram positive for IE, documented by an oscillating intracardiac mass on a valve or on supporting structures, in the path of regurgitant jets, or on implanted material, in the absence of an alternative anatomic explanation Myocardial abscessDevelopment of partial dehiscence of a prosthetic valveNew-onset valvular regurgitation

Minor criteria for IE include the following:

Predisposing heart condition or intravenous drug useFever of 38°C (100.4°F) or higherVascular phenomenon, including major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, or Janeway lesions Immunologic phenomenon such as glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factorPositive blood culture results not meeting major criteria or serologic evidence of active infection with an organism consistent with IE Echocardiogram results consistent with IE but not meeting major echocardiographic criteria

A definitive clinical diagnosis can be made based on the following:

2 major criteria1 major criterion and 3 minor criteria5 minor criteria

See Workup for more detail.

Management

Antibiotics remain the mainstay of treatment for IE. Three to five sets of blood cultures should be obtained within 60-90 minutes, followed by the infusion of the appropriate antibiotic regimen. By necessity, the initial antibiotic choice is empiric in nature, determined by clinical history and physical examination findings.

Empiric antibiotic therapy is chosen based on the most likely infecting organisms. Native valve endocarditis (NVE) has often been treated with penicillin G and gentamicin for synergistic coverage of streptococci. Patients with a history of intravenous drug use have been treated with nafcillin and gentamicin to cover for methicillin-sensitive staphylococci. The emergence of methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant streptococci has led to a change in empiric treatment, with liberal substitution of vancomycin in lieu of a penicillin antibiotic.

See Treatment and Medication for more detail.

Image libraryAcute bacterial endocarditis caused by Staphylococcus aureus with perforation of the aortic valve and aortic valve vegetations. Courtesy of Janet Jones, MD, Laboratory Service, Wichita Veterans Administration Medical Center. NextBackground

Infective endocarditis (IE) is defined as an infection of the endocardial surface of the heart, which may include one or more heart valves, the mural endocardium, or a septal defect. Its intracardiac effects include severe valvular insufficiency, which may lead to intractable congestive heart failure and myocardial abscesses. IE also produces a wide variety of systemic signs and symptoms through several mechanisms, including both sterile and infected emboli and various immunological phenomena.[5, 6, 7]

The history of IE can be divided into several eras. In 1674, Lazaire Riviere first described the gross autopsy findings of the disease in his monumental work Opera medica universa. In 1885, William Osler presented the first comprehensive description of endocarditis in English. Lerner and Weinstein presented a thorough discussion of this disease in modern times in their landmark series of articles, “Infective Endocarditis in the Antibiotic Era,” published in 1966 in the New England Journal of Medicine.[8, 9, 10]

IE currently can be described as infective endocarditis in the era of intravascular devices, as infection of intravascular lines has been determined to be the primary risk factor for Staphylococcus aureus bloodstream infections (BSIs). S aureus has become the primary pathogen of endocarditis.[11]

IE generally occurs as a consequence of nonbacterial thrombotic endocarditis, which results from turbulence or trauma to the endothelial surface of the heart. A transient bacteremia then seeds the sterile platelet/fibrin thrombus, with IE as the end result. Pathologic effects due to infection can include local tissue destruction and embolic phenomena. In addition, secondary autoimmune effects, such as immune complex glomerulonephritis and vasculitis, can occur. (See Pathophysiology.)

IE remains a diagnostic and therapeutic challenge. Its manifestations may be muted by the indiscriminate use of antimicrobial agents or by underlying conditions in frail and elderly individuals or immunosuppressed persons. (See Diagnosis.)

Effective therapy has become progressively more difficult to achieve because of the proliferation of implanted biomechanical devices and the rise in the number of resistant organisms. Antibiotic prophylaxis has probably had little effect in decreasing the incidence of IE. (See Treatment and Management.)

For other discussions on IE, see Pediatric Bacterial Endocarditis, Infectious Endocarditis, Neurological Sequelae of Infective Endocarditis, and Antibiotic Prophylactic Regimens for Endocarditis.

Types of infective endocarditis

Endocarditis has evolved into several variations, keeping it near the top of the list of diseases that must not be misdiagnosed or overlooked. Endocarditis can be broken down into the following categories:

Native valve endocarditis (NVE), acute and subacuteProsthetic valve endocarditis (PVE),[12] early and late Intravenous drug abuse (IVDA) endocarditis

Other terms commonly used to classify types of IE include pacemaker IE and nosocomial IE (NIE).

The classic clinical presentation and clinical course of IE has been characterized as either acute or subacute. Indiscriminate antibiotic usage and an increase in immunosuppressed patients have blurred the distinction between these 2 major types; however, the classification still has clinical merit.[13]

Acute NVE frequently involves normal valves and usually has an aggressive course. It is a rapidly progressive illness in persons who are healthy or debilitated. Virulent organisms, such as S aureus and group B streptococci, are typically the causative agents of this type of endocarditis. Underlying structural valve disease may not be present.

Subacute NVE typically affects only abnormal valves. Its course, even in untreated patients, is usually more indolent than that of the acute form and may extend over many months. Alpha-hemolytic streptococci or enterococci, usually in the setting of underlying structural valve disease, typically are the causative agents of this type of endocarditis.

PVE accounts for 10-20% of cases of IE. Eventually, 5% of mechanical and bioprosthetic valves become infected. Mechanical valves are more likely to be infected within the first 3 months of implantation, and, after 1 year, bioprosthetic valves are more likely to be infected. The valves in the mitral valve position are more susceptible than those in the aortic areas.[12]

Early PVE occurs within 60 days of valve implantation. Traditionally, coagulase-negative staphylococci, gram-negative bacilli, and Candida species have been the common infecting organisms. Late PVE occurs 60 days or more after valve implantation. Staphylococci, alpha-hemolytic streptococci, and enterococci are the common causative organisms. Recent data suggest that S aureus may now be the most common infecting organism in both early and late PVE.[14]

In 75% of cases of IVDA IE, no underlying valvular abnormalities are noted, and 50% of these infections involve the tricuspid valve.[15] S aureus is the most common causative organism.

Analogous to PVE are infections of implantable pacemakers and cardioverter-defibrillators. Usually, these devices are infected within a few months of implantation. Infection of pacemakers includes that of the generator pocket (the most common), infection of the proximal leads, and infection of the portions of the leads in direct contact with the endocardium.

This last category represents true pacemaker IE, is the least common infectious complication of pacemakers (0.5% of implanted pacemakers), and is the most challenging to treat. Of pacemaker infections, 75% are produced by staphylococci, both coagulase-negative and coagulase-positive.

NIE is defined as an infection that manifests 48 hours after the patient is hospitalized or that is associated with a hospital, based on a procedure performed within 4 weeks of clinical disease onset. The term healthcare-associated infective endocarditis (HCIE) is preferable to NIE, since it is inclusive of all sites that deliver patient care, such as hemodialysis centers. The term NIE should be applied to cases of IE acquired in the hospital. An appropriate alternative term would be iatrogenic IE.

Two types of NIE have been described. The right-sided variety affects a valve that has been injured by placement of an intravascular line (eg, Swan-Ganz catheter). Subsequently, the valve is infected by a nosocomial bacteremia. The second type develops in a previously damaged valve and is more likely to occur on the left side. S aureus has been the predominant pathogen of NIE/HCIE since the recent prevalence of intravascular devices. Enterococci are second most commonly isolated pathogens. These usually arise from a genitourinary source.

Evolution of clinical characteristics of infective endocarditis

Since the 1960s, the clinical characteristics of IE have changed significantly. The dramatic “graying” of the disease and the increase in recreational drug use and proliferation of invasive vascular procedures underlie this phenomenon. Varieties of IE that were uncommon in the early antibiotic era have become prominent. Cases of NIE, IVDA IE, and PVE have markedly increased. Valvular infections have entered the era of IE caused by intravascular devices and procedures.

The underlying valvular pathology has also changed. Rheumatic heart disease currently accounts for less than 20% of cases, and 6% of patients with rheumatic heart disease eventually develop IE. Approximately 50% of elderly patients have calcific aortic stenosis as the underlying pathology. Congenital heart disease accounts for 15% of cases, with the bicuspid aortic valve being the most common example.

Other contributing congenital abnormalities include ventricular septal defects, patent ductus arteriosus, and tetralogy of Fallot. Atrial septal defect (secundum variety) is rarely associated with IE. Mitral valve prolapse is the most common predisposing condition found in young adults and is the predisposing condition in 30% of cases of NVE in this age group. IE complicates 5% of cases of asymmetrical septal hypertrophy, usually involving the mitral valve.

PreviousNextPathophysiology

IE develops most commonly on the mitral valve, closely followed in descending order of frequency by the aortic valve, the combined mitral and aortic valve, the tricuspid valve, and, rarely, the pulmonic valve. Mechanical prosthetic and bioprosthetic valves exhibit equal rates of infection.

All cases of IE develop from a commonly shared process, as follows:

Bacteremia (nosocomial or spontaneous) that delivers the organisms to the surface of the valveAdherence of the organismsEventual invasion of the valvular leaflets

The common denominator for adherence and invasion is nonbacterial thrombotic endocarditis, a sterile fibrin-platelet vegetation. The development of subacute IE depends on a bacterial inoculum sufficient to allow invasion of the preexistent thrombus. This critical mass is the result of bacterial clumping produced by agglutinating antibodies.

In acute IE, the thrombus may be produced by the invading organism (ie, S aureus) or by valvular trauma from intravenous catheters or pacing wires (ie, NIE/HCIE). S aureus can invade the endothelial cells (endotheliosis) and increase the expression of adhesion molecules and of procoagulant activity on the cellular surface. Nonbacterial thrombotic endocarditis may result from stress, renal failure, malnutrition, systemic lupus erythematosus, or neoplasia.

The Venturi effect also contributes to the development and location of nonbacterial thrombotic endocarditis. This principle explains why bacteria and the fibrin-platelet thrombus are deposited on the sides of the low-pressure sink that lies just beyond a narrowing or stenosis.

In patients with mitral insufficiency, bacteria and the fibrin-platelet thrombus are located on the atrial surface of the valve. In patients with aortic insufficiency, they are located on the ventricular side. In these examples, the atria and ventricles are the low-pressure sinks. In the case of a ventricular septal defect, the low-pressure sink is the right ventricle and the thrombus is found on the right side of the defect.

Nonbacterial thrombotic endocarditis may also form on the endocardium of the right ventricle, opposite the orifice that has been damaged by the jet of blood flowing through the defect (ie, the MacCallum patch).

The microorganisms that most commonly produce endocarditis (ie, S aureus; Streptococcus viridans; group A, C, and G streptococci; enterococci) resist the bactericidal action of complement and possess fibronectin receptors for the surface of the fibrin-platelet thrombus. Among the many other characteristics of IE-producing bacteria demonstrated in vitro and in vivo, some features include the following:

Increased adherence to aortic valve leaflet disks by enterococci, S viridans, and S aureusMucoid-producing strains of S aureusDextran-producing strains of S viridansS viridans and enterococci that possess FimA surface adhesinPlatelet aggregation by S aureus and S viridans and resistance of S aureus to platelet microbicidal proteins

The pathogenesis of pacemaker IE is similar. Shortly after implantation, the development of a fibrin-platelet thrombus (similar to the nonbacterial thrombotic endocarditis described above) involves the generator box and conducting leads. After 1 week, the connective tissue proliferates, partially embedding the leads in the wall of the vein and endocardium. This layer may offer partial protection against infection during a bacteremia.

Bacteremia (either spontaneous or due to an invasive procedure) infects the sterile fibrin-platelet vegetation described above. BSIs develop from various extracardiac types of infection, such as pneumonias or pyelonephritis, but most commonly from gingival disease. Of those with high-grade gingivitis, 10% have recurrent transient bacteremias (usually streptococcal species). Most cases of subacute disease are secondary to the bacteremias that develop from the activities of daily living (eg, brushing teeth, bowel movements).

The skin is quite resistant to S aureus infection due in great part to its production of antimicrobial peptides. Soong et al discovered that, in vitro, the secretion of alpha toxin by S aureus allows the organism to successfully penetrate the keratinocyte layer. This could explain the presence of staphylococcal bacteremia in the absence of any gross damage to the epithelial layer.[16]

Bacteremia can result from various invasive procedures, ranging from oral surgery to sclerotherapy of esophageal varices to genitourinary surgeries to various abdominal operations. The potential for invasive procedures to produce a bacteremia varies greatly. Procedures, rates, and organisms are as follows:

Endoscopy - Rate of 0-20%; coagulase-negative staphylococci (CoNS), streptococci, diphtheroidsColonoscopy - Rate of 0-20%; Escherichia coli, Bacteroides speciesBarium enema - Rate of 0-20%; enterococci, aerobic and anaerobic gram-negative rodsDental extractions - Rate of 40-100%; S viridansTransurethral resection of the prostate - Rate of 20-40%; coliforms, enterococci, S aureusTransesophageal echocardiography - Rate of 0-20%; S viridans, anaerobic organisms, streptococci

The incidence of nosocomial bacteremias, mostly associated with intravascular lines, has more than doubled in the last few years. Up to 90% of BSIs caused by these devices are secondary to the placement of various types of central venous catheters. Hickman and Broviac catheters are associated with the lowest rates, presumably because of their Dacron cuffs. Peripherally placed central venous catheters are associated with similar rates.

Intravascular catheters are infected from 1 of the following 4 sources:

Infection of the insertion siteInfection of the catheterBacteremia arising from another siteContamination of the infused solution

Bacterial adherence to intravascular catheters depends on the response of the host to the presence of this foreign body, the properties of the organism itself, and the position of the catheter. Within a few days of insertion, a sleeve of fibrin and fibronectin is deposited on the catheter. S aureus adheres to the fibrin component.

S aureus also produces an infection of the endothelial cells (endotheliosis), which is important in producing the continuous bacteremia of S aureus BSIs. Endotheliosis may explain many cases of persistent methicillin-susceptible S aureus (MSSA) and methicillin-resistant S aureus (MRSA) catheter-related BSIs without an identifiable cause.

S aureus catheter-related BSIs occur even after an infected catheter is removed, apparently attributable to specific virulence factors of certain strains of S aureus that invade the adjacent endothelial cells. At some point, the staphylococci re-enter the bloodstream, resulting in bacteremia.[17]

Four days after placement, the risk of infection markedly increases. Lines positioned in the internal jugular are more prone to infection than those placed in the subclavian vein. Colonization of the intracutaneous tract is the most likely source of short-term catheter-related BSIs. Among lines in place for more than 2 weeks, infection of the hub is the major source of bacteremia. In some cases, the infusion itself may be a reservoir of infection.

Colonization of heart valves by microorganisms is a complex process. Most transient bacteremias are short-lived, are without consequence, and are often not preventable. Bacteria rarely adhere to an endocardial nidus before the microorganisms are removed from the circulation by various host defenses.

Once microorganisms do establish themselves on the surface of the vegetation, the process of platelet aggregation and fibrin deposition accelerate at the site. As the bacteria multiply, they are covered by ever-thickening layers of platelets and thrombin, which protect them from neutrophils and other host defenses. Organisms deep in the vegetation hibernate because of the paucity of available nutrients and are therefore less susceptible to bactericidal antimicrobials that interfere with bacterial cell wall synthesis.

Complications of subacute endocarditis result from embolization, slowly progressive valvular destruction, and various immunological mechanisms. The pathological picture of subacute IE is marked by valvular vegetations in which bacteria colonies are present both on and below the surface.

The cellular reaction in SBE is primarily that of mononuclear cells and lymphocytes, with few polymorphonuclear cells. The surface of the valve beneath the vegetation shows few organisms. Proliferation of capillaries and fibroblasts is marked. Areas of healing are scattered among areas of destruction. Over time, the healing process falls behind, and valvular insufficiency develops secondary to perforation of the cusps and damage to the chordae tendineae. Compared with acute disease, little extension of the infectious process occurs beyond the valvular leaflets.

levels of agglutinating and complement-fixing bactericidal antibodies and cryoglobulins are markedly increased in patients with subacute endocarditis. Many of the extracardiac manifestations of this form of the disease are due to circulating immune complexes. Among these include glomerulonephritis, peripheral manifestations (eg, Osler nodes, Roth spots, subungual hemorrhages), and, possibly, various musculoskeletal abnormalities. Janeway lesions usually arise from infected microemboli.

The microscopic appearance of acute bacterial endocarditis differs markedly from that of subacute disease. Vegetations that contain no fibroblasts develop rapidly, with no evidence of repair. Large amounts of both polymorphonuclear leukocytes and organisms are present in an ever-expanding area of necrosis. This process rapidly produces spontaneous rupture of the leaflets, of the papillary muscles, and of the chordae tendineae.

The complications of acute bacterial endocarditis result from intracardiac disease and metastatic infection produced by suppurative emboli. Because of their shortened course, immunological phenomena are not a part of acute IE.

PreviousNextEtiology

The different types of IE have varying causes and involve different pathogens.

Native valve endocarditis

The following are the main underlying causes of NVE:

Rheumatic valvular disease (30% of NVE) - Primarily involves the mitral valve followed by the aortic valveCongenital heart disease (15% of NVE) - Underlying etiologies include a patent ductus arteriosus, ventricular septal defect, tetralogy of Fallot, or any native or surgical high-flow lesion. Mitral valve prolapse with an associated murmur (20% of NVE)Degenerative heart disease - Including calcific aortic stenosis due to a bicuspid valve, Marfan syndrome, or syphilitic disease

Approximately 70% of infections in NVE are caused by Streptococcus species, including S viridans, Streptococcus bovis, and enterococci. Staphylococcus species cause 25% of cases and generally demonstrate a more aggressive acute course (see the images below).

Prosthetic valve endocarditis

Early PVE, which presents shortly after surgery, has a different bacteriology and prognosis than late PVE, which presents in a subacute fashion similar to NVE.

Infection associated with aortic valve prostheses is particularly associated with local abscess and fistula formation, and valvular dehiscence. This may lead to shock, heart failure, heart block, shunting of blood to the right atrium, pericardial tamponade, and peripheral emboli to the central nervous system and elsewhere.

Early PVE may be caused by a variety of pathogens, including S aureus and S epidermidis. These nosocomially acquired organisms are often methicillin-resistant (eg, MRSA).[18] Late disease is most commonly caused by streptococci. Overall, CoNS are the most frequent cause of PVE (30%).

S aureus causes 17% of early PVE and 12% of late PVE. Corynebacterium, nonenterococcal streptococci, fungi (eg, C albicans, Candida stellatoidea, Aspergillus species), Legionella, and the HACEK (ie, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae) organisms cause the remaining cases.

IVDA infective endocarditis

Diagnosis of endocarditis in IV drug users can be difficult and requires a high index of suspicion. Two thirds of patients have no previous history of heart disease or murmur on admission. A murmur may be absent in those with tricuspid disease, owing to the relatively small pressure gradient across this valve. Pulmonary manifestations may be prominent in patients with tricuspid infection: one third have pleuritic chest pain, and three quarters demonstrate chest radiographic abnormalities.

S aureus is the most common (S aureus infections and has been associated with previous hospitalizations, long-term addiction, and nonprescribed antibiotic use. Groups A, C, and G streptococci and enterococci are also recovered from patients with IVDA IE.

Currently, gram-negative organisms are involved infrequently. P aeruginosa[19] and the HACEK family are the most common examples.

Nosocomial/healthcare-associated infective endocarditis

Endocarditis may be associated with new therapeutic modalities involving intravascular devices such as central or peripheral intravenous catheters, rhythm control devices such as pacemakers and defibrillators, hemodialysis shunts and catheters, and chemotherapeutic and hyperalimentation lines.[20, 21] These patients tend to have significant comorbidities, more advanced age, and predominant infection with S aureus. The mortality rate is high in this group.

The organisms that cause NIE/HCIE obviously are related to the type of underlying bacteremia. The gram-positive cocci (ie, S aureus, CoNS, enterococci, nonenterococcal streptococci) are the most common pathogens.

Fungal endocarditis

Fungal endocarditis is found in intravenous drug users and intensive care unit patients who receive broad-spectrum antibiotics.[22] Blood cultures are often negative, and diagnosis frequently is made after microscopic examination of large emboli.

Clinical features associated with different pathogens

Different causative organisms tend to give rise to varying clinical manifestations of IE, as shown in the Table below.

Table 1. Clinical Features of Infective Endocarditis According to Causative Organism (Open Table in a new window)

Causative Organism(s) Clinical Features of IE Staphylococcus aureusOverall, S aureus infection is the most common cause of IE, including PVE, acute IE, and IVDA IE.Approximately 35-60.5% of staphylococcal bacteremias are complicated by IE.More than half the cases are not associated with underlying valvular disease.The mortality rate of S aureus IE is 40-50%.S aureus infection is the second most common cause of nosocomial BSIs, second only to CoNS infection.The incidence of MRSA infections, both the hospital- and community-acquired varieties, has dramatically increased (50% of isolates). Sixty percent of individuals are intermittent carriers of MRSA or MSSA .The primary risk factor for S aureus BSI is the presence of intravascular lines. Other risk factors include cancer, diabetes, corticosteroid use, IVDA, alcoholism, and renal failure. The realization that approximately 50% of hospital- and community-acquired staphylococcal bacteremias arise from infected vascular catheters has led to the reclassification of staphylococcal BSIs. BSIs are acquired not only in the hospital but also in any type of health care facility (eg, nursing home, dialysis center). Of S aureus bacteremia cases in the United States, 7.8% (200,000) per year are associated with intravascular catheters.Streptococcus viridansThis organism accounts for approximately 50-60% of cases of subacute disease.Most clinical signs and symptoms are mediated immunologically.Streptococcus intermedius groupThese infections may be acute or subacute.S intermedius infection accounts for 15% of streptococcal IE cases.Members of the S intermedius group, especially S anginosus, are unique among the streptococci in that they can actively invade tissue and form abscesses, often in the CNS.AbiotrophiaApproximately 5% of subacute cases of IE are due to infection with Abiotrophia species.They require metabolically active forms of vitamin B-6 for growth.This type of IE is associated with large vegetations that lead to embolization and a high rate of posttreatment relapse.Group D streptococciMost cases are subacute.The source is the gastrointestinal or genitourinary tract.It is the third most common cause of IE.They pose major resistance problems for antibiotics.Nonenterococcal group DThe clinical course is subacute.Infection often reflects underlying abnormalities of the large bowel (eg, ulcerative colitis, polyps, cancer).The organisms are sensitive to penicillin.Group B streptococciAcute disease develops in pregnant patients and older patients with underlying diseases (eg, cancer, diabetes, alcoholism).The mortality rate is 40%.Complications include metastatic infection, arterial thrombi, and congestive heart failure.It often requires valve replacement for cure.Group A, C, and G streptococciAcute disease resembles that of S aureus IE (30-70% mortality rate), with suppurative complications.Group A organisms respond to penicillin alone.Group C and G organisms require a combination of synergistic antibiotics (as with enterococci).Coagulase-negative S aureusThis causes subacute disease.It behaves similarly to S viridans infection.It accounts for approximately 30% of PVE cases and less than 5% of NVE cases.[23] Pseudomonas aeruginosaThis is usually acute, except when it involves the right side of the heart in IVDA IE.Surgery is commonly required for cure.HACEK (ie, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae)These organisms usually cause subacute disease.They account for approximately 5% of IE cases.They are the most common gram-negative organisms isolated from patients with IE.Complications may include massive arterial emboli and congestive heart failure.Cure requires ampicillin, gentamicin, and surgery.FungalThese usually cause subacute disease.The most common organism of both fungal NVE and fungal PVE is Candida albicans.Fungal IVDA IE is usually caused by Candida parapsilosis or Candida tropicalis.Aspergillus species are observed in fungal PVE and NIE.BartonellaThe most commonly involved species is Bartonella quintana.IE typically develops in homeless males who have extremely substandard hygiene. Bartonella must be considered in cases of culture-negative endocarditis among homeless individuals.Multiple pathogens (polymicrobial)Pseudomonas and enterococci are the most common combination of organisms.It is observed in cases of IVDA IEThe cardiac surgery mortality rate is twice that associated with single-agent IE.[24] Risk factors

The most significant risk factor for IE is residual valvular damage caused by a previous attack of endocarditis.[25, 20]

Many possible risk factors for the development of pacemaker IE have been described, including diabetes mellitus, age, and use of anticoagulants and corticosteroids. The evidence for these is conflicting. The major risk factor is probably surgical intervention to any part of the pacemaker system, especially elective battery replacements. The rate of infection associated with battery replacements is approximately 5 times that of the initial implantation (6.5% vs 1.4%).

Other significant risk factors for pacemaker IE include the development of a postoperative hematoma, the inexperience of the surgeon, and a preceding temporary transvenous pacing.

PreviousNextEpidemiology

In the United States, the 2009 incidence of IE was approximately 12.7 cases per 100,000 persons per year.[26] The age-adjusted hospital admission rate has increased 2.4% annually from 1998-2009. This rate has risen significantly from that of the previous 50 years (2-4 cases per 100,000 persons per year).[27] The incidence of IE in other countries is similar to that in the United States. From 1998-2009, the proportion of patients with intracardiac devices increased from 13.3% to 18.9%, while the proportion of cases with a background of HIV infection or HIV drug abuse fell.

Between 1998 and 2009, the mean age of patients has risen from 58.6 to 60.8 years.[26] Currently, more than 50% of patients are older than 50 years.[20] Mendiratta et al, in their retrospective study of hospital discharges from 1993-2003 of patients aged 65 years and older with a primary or secondary diagnosis of IE, found that hospitalizations for IE increased 26%, from 3.19 per 10,000 elderly patients in 1993 to 3.95 per 10,000 in 2003.[28] This increase in age has continued, with the mean age of patients in 2009 at 60.8 years.[26]

IE is 3 times as common in males as in females. It has no racial predilection.

PreviousNextPrognosis

Prognosis largely depends on whether or not complications develop. If left untreated, IE is generally fatal. Early detection and appropriate treatment of this uncommon disease can be lifesaving. The overall mortality rate has remained stable at 14.5%.[26]

Cure rates for appropriately managed (including both medical and surgical therapies) NVE are as follows:

For S viridans and S bovis infection, the rate is 98%.For enterococci and S aureus infection in individuals who abuse intravenous drugs, the rate is 90%.For community-acquired S aureus infection in individuals who do not abuse intravenous drugs, the rate is 60-70%.For infection with aerobic gram-negative organisms, the rate is 40-60%.For infection with fungal organisms, the rate is lower than 50%.

For PVE, the cure rates are as follows:

Rates are 10-15% lower for each of the above categories, for both early and late PVE.Surgery is required far more frequently.Approximately 60% of early CoNS PVE cases and 70% of late CoNS PVE cases are curable.

Anecdotal reports describe the resolution of right-sided valvular infection caused by S aureus infection in individuals who abuse intravenous drugs after just a few days of oral antibiotics.

The role of early valvular surgery in reducing mortality among patients with IE has become somewhat clearer. Challenges to resolving this question include the necessity of performing multicentered studies with an apparent difficulty of ensuring that the patients' preoperative assessments and surgical approaches are comparable. The largest study to date indicates that in cases of IE complicated by heart failure, valvular surgery reduces the 1-year mortality rate.[29] More recent studies document that early surgery in patients, especially those with large vegetations, significantly reduces the risk of death from any cause that from embolic events.[30, 31]

Mortality rates in NVE range from 16-27%. Mortality rates in patients with PVE are higher. More than 50% of these infections occur within 2 months after surgery. The fatality rate of pacemaker IE ranges up to 34%.[32]

Increased mortality rates are associated with increased age,[33] infection involving the aortic valve, development of congestive heart failure, central nervous system (CNS) complications, and underlying disease such as diabetes mellitus. Catastrophic neurological events of all types due to IE are highly predictive of morbidity and mortality.[34]

Mortality rates also vary with the infecting organism. Acute endocarditis due to S aureus is associated with a high mortality rate (30-40%), except when it is associated with IV drug use.[14, 35] Endocarditis due to streptococci has a mortality rate of approximately 10%.

PreviousNextPatient Education

Surveys indicate that an appallingly small number of patients who are at risk for developing IE have an understanding of antibiotic and nonpharmacologic (ie, appropriate oral hygiene) principles. Drug rehabilitation for patients who use IV drugs is critical.

The United Kingdom’s National Institute for Health and Clinical Excellence (NICE) addresses patient education in its 2008 guideline on prophylaxis against IE in adults and children undergoing interventional procedures. The NICE’s guideline recommends that health care professionals teach patients about the symptoms of IE and the risks of nonmedical invasive procedures such as body piercing and tattooing, explain the benefits and risks of antibiotic prophylaxis and the reasons that it is no longer routine, and emphasize the need to maintain good oral health.[36]

For patient education information, see the Heart Center, as well as Tetralogy of Fallot.

PreviousProceed to Clinical Presentation , Infective Endocarditis

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Aortic Stenosis

Practice Essentials

Aortic stenosis is the obstruction of blood flow across the aortic valve. Among symptomatic patients with medically treated moderate-to-severe aortic stenosis, mortality from the onset of symptoms is approximately 25% at 1 year and 50% at 2 years. Symptoms of aortic stenosis usually develop gradually after an asymptomatic latent period of 10-20 years.

Essential update: Expanded FDA labeling for transcatheter valve allows alternative access sites

In September 2013, the FDA approved new labeling for the Sapien transcatheter valve, which eliminates references to specific access sites used when implanting the valves (ie, transfemoral and transapical approaches) and allows the use of alternative access sites (eg, subclavian approach).[1, 2] The change in labeling was supported by data from the Transcatheter Valve Therapy Registry and European registries.

Signs and symptoms

The classic triad of symptoms in patients with aortic stenosis is as follows[3] :

Chest pain: Angina pectoris in patients with aortic stenosis is typically precipitated by exertion and relieved by restHeart failure: Symptoms include paroxysmal nocturnal dyspnea, orthopnea, dyspnea on exertion, and shortness of breathSyncope: Often occurs upon exertion when systemic vasodilatation in the presence of a fixed forward stroke volume causes the arterial systolic blood pressure to decline

Systolic hypertension can coexist with aortic stenosis. However, a systolic blood pressure higher than 200 mm Hg is rare in patients with critical aortic stenosis.

In severe aortic stenosis, the carotid arterial pulse typically has a delayed and plateaued peak, decreased amplitude, and gradual downslope (pulsus parvus et tardus).

Other symptoms of aortic stenosis include the following:

Pulsus alternans: Can occur in the presence of left ventricular systolic dysfunctionHyperdynamic left ventricle: Unusual; suggests concomitant aortic regurgitation or mitral regurgitationSoft or normal S1Diminished or absent A2: The presence of a normal or accentuated A2 speaks against the existence of severe aortic stenosisParadoxical splitting of the S2: Resulting from late closure of A2Accentuated P2: In the presence of secondary pulmonary hypertensionEjection click: Common in children and young adults with congenital aortic stenosisProminent S4: Resulting from forceful atrial contraction into a hypertrophied left ventricleSystolic murmur: The classic crescendo-decrescendo systolic murmur of aortic stenosis begins shortly after the first heart sound; the intensity increases toward midsystole and then decreases, with the murmur ending just before the second heart sound

See Clinical Presentation for more detail.

Diagnosis

The following studies are used in the diagnosis and assessment of aortic stenosis:

Serum electrolyte levelsCardiac biomarkersComplete blood countB-type natriuretic peptide: May provide incremental prognostic information for predicting symptom onset in asymptomatic patients with severe aortic stenosis[4] Electrocardiography: Serial ECG can demonstrate the progression of aortic stenosisChest radiographyEchocardiography: 2-dimensional and DopplerCardiac catheterization: Can be used if clinical findings are inconsistent with echocardiogram resultsCoronary angiographyRadionuclide ventriculography: May provide information on LV functionExercise stress testing: Contraindicated in symptomatic patients with severe aortic stenosis

See Workup for more detail.

Management

The only definitive treatment for aortic stenosis is aortic valve replacement. The development of symptoms due to this condition provides a clear indication for replacement.[5, 6]

Emergency care

A patient presenting with uncontrolled heart failure should be treated supportively with oxygen, cardiac and oximetry monitoring, intravenous access, loop diuretics, nitrates (remembering the potential nitrate sensitivity of patients with aortic stenosis), morphine (as needed and tolerated), and noninvasive or invasive ventilatory support (as indicated). Patients with severe heart failure due to aortic stenosis that is resistant to medical management should be considered for urgent surgery.

Pharmacologic therapy

Agents used in the treatment of patients with aortic stenosis include the following:

Digitalis, diuretics, and angiotensin-converting enzyme (ACE) inhibitors: Can be cautiously used in patients with pulmonary congestion Vasodilators: May be used for heart failure and for hypertension but should also be employed with extreme cautionDigoxin, diuretics, ACE inhibitors, or angiotensin receptor blockers[6] : Recommended by the European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS) guidelines for patients with heart failure symptoms who are not suitable candidates for surgery or transcatheter aortic valve implantation

Aortic valve replacement

According to American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, candidates for aortic valve replacement include the following patients[7] :

Symptomatic patients with severe aortic stenosisPatients with severe aortic stenosis undergoing coronary artery bypass surgeryPatients with severe aortic stenosis undergoing surgery on the aorta or other heart valvesPatients with severe aortic stenosis and LV systolic dysfunction (ejection fraction

Percutaneous balloon valvuloplasty

Percutaneous balloon valvuloplasty is used as a palliative measure in critically ill adult patients who are not surgical candidates or as a bridge to aortic valve replacement in critically ill patients.

See Treatment and Medication for more detail.

Image libraryCalcific aortic stenosis (parasternal long-axis and short-axis views). NextBackground

Aortic stenosis is the obstruction of blood flow across the aortic valve. Aortic stenosis has several etiologies, including congenital (unicuspid or bicuspid valve), calcific (due to degenerative changes), and rheumatic. Degenerative calcific aortic stenosis is now the leading indication for aortic valve replacement. The favorable long-term outcome following aortic valve surgery and the relatively low operative risk emphasize the importance of an accurate and timely diagnosis (see Prognosis).

Stenotic valves are shown in the images below. Symptoms of aortic stenosis usually develop gradually after an asymptomatic latent period of 10-20 years. Exertional dyspnea or fatigue is the most common initial complaint. Ultimately, most patients experience the classic triad of chest pain, heart failure, and syncope (see History).

Two-dimensional (2D) Doppler echocardiography is the imaging modality of choice to diagnose and estimate the severity of aortic stenosis and localize the level of obstruction (see Workup). The only definitive treatment for aortic stenosis is aortic valve replacement (see Treatment and Management).

Go to Pediatric Valvar Aortic Stenosis, Pediatric Subvalvar Aortic Stenosis, and Pediatric Supravalvar Aortic Stenosis for more complete information on these topics.

PreviousNextPathophysiology

When the aortic valve becomes stenotic, resistance to systolic ejection occurs and a systolic pressure gradient develops between the left ventricle and the aorta. This outflow obstruction leads to an increase in left ventricular (LV) systolic pressure. As a compensatory mechanism to normalize LV wall stress, LV wall thickness increases by parallel replication of sarcomeres, producing concentric hypertrophy. At this stage, the chamber is not dilated and ventricular function is preserved, although diastolic compliance is reduced.

Eventually, however, LV end-diastolic pressure (LVEDP) rises, which causes a corresponding increase in pulmonary capillary arterial pressures and a decrease in cardiac output due to diastolic dysfunction. The contractility of the myocardium may also diminish, which leads to a decrease in cardiac output due to systolic dysfunction. Ultimately, heart failure develops.

In most patients with aortic stenosis, LV systolic function is preserved and cardiac output is maintained for many years despite an elevated LV systolic pressure. Although cardiac output is normal at rest, it often fails to increase appropriately during exercise, which may result in exercise-induced symptoms.

Diastolic dysfunction may occur as a consequence of impaired LV relaxation and/or decreased LV compliance, as a result of increased afterload, LV hypertrophy, or myocardial ischemia. LV hypertrophy often regresses following relief of valvular (also called valvular) obstruction. However, some individuals develop extensive myocardial fibrosis, which may not resolve despite regression of hypertrophy.

In patients with severe aortic stenosis, atrial contraction plays a particularly important role in diastolic filling of the left ventricle. Thus, development of atrial fibrillation in aortic stenosis often leads to heart failure due to an inability to maintain cardiac output.

Increased LV mass, increased LV systolic pressure, and prolongation of the systolic ejection phase all elevate the myocardial oxygen requirement, especially in the subendocardial region. Although coronary blood flow may be normal when corrected for LV mass, coronary flow reserve is often reduced.

Myocardial perfusion is thus compromised by the relative decline in myocardial capillary density and by a reduced diastolic transmyocardial (coronary) perfusion gradient due to elevated LV diastolic pressure. Therefore, the subendocardium is susceptible to underperfusion, which results in myocardial ischemia.

Angina results from a concomitant increased oxygen requirement by the hypertrophic myocardium and diminished oxygen delivery secondary to diminished coronary flow reserve, decreased diastolic perfusion pressure, and relative subendocardial myocardial ischemia.

PreviousNextEtiology

Most cases of aortic stenosis are due to the obstruction at the valvular level. Common causes are summarized in Table 1.

Table 1. Common Causes of Aortic Stenosis Among Patients Requiring Surgery (Open Table in a new window)

Age Age >70 years (n=322) Bicuspid AV (50%)

Postinflammatory (25%)

Degenerative (18%)

Unicommissural (3%)

Hypoplastic (2%)

Indeterminate (2%)

Degenerative (48%)

Bicuspid (27%)

Postinflammatory (23%)

Hypoplastic (2%)

Valvular aortic stenosis can be either congenital or acquired.

Congenital valvular aortic stenosis

Congenitally unicuspid, bicuspid, tricuspid, or even quadricuspid valves may be the cause of aortic stenosis. In neonates and infants younger than 1 year, a unicuspid valve can produce severe obstruction and is the most common anomaly in infants with fatal valvular aortic stenosis. In patients younger than 15 years, unicuspid valves are most frequent in cases of symptomatic aortic stenosis.

In adults who develop symptoms from congenital aortic stenosis, the problem is usually a bicuspid valve. Bicuspid valves do not cause significant narrowing of the aortic orifice during childhood. The altered architecture of the bicuspid aortic valve induces turbulent flow with continuous trauma to the leaflets, ultimately resulting in fibrosis, increased rigidity and calcification of the leaflets, and narrowing of the aortic orifice in adulthood.

A cohort study by Tzemos et al of 642 ambulatory adults with bicuspid aortic valves found that during the mean follow-up duration of 9 years, survival rates were not lower than for the general population. However, young adults with bicuspid aortic valve had a high likelihood of eventually requiring aortic valve intervention.[8]

Congenitally malformed tricuspid aortic valves with unequally sized cusps and commissural fusion (“functionally bicuspid” valves) can also cause turbulent flow leading to fibrosis and, ultimately, to calcification and stenosis. Clinical manifestations of congenital aortic stenosis in adults usually appear after the fourth decade of life.

Acquired valvular aortic stenosis

The main causes of acquired aortic stenosis include degenerative calcification and, less commonly, rheumatic heart disease.

Degenerative calcific aortic stenosis (also called senile calcific aortic stenosis) involves progressive calcification of the leaflet bodies, resulting in limitation of the normal cusp opening during systole. This represents a consequence of long-standing hemodynamic stress on the valve and is currently the most frequent cause of aortic stenosis requiring aortic valve replacement. The calcification may also involve the mitral annulus or extend into the conduction system, resulting in atrioventricular or intraventricular conduction defects.

Risk factors for degenerative calcific aortic stenosis include hypertension, hypercholesterolemia, diabetes mellitus, and smoking. The available data suggest that the development and progression of the disease are due to an active disease process at the cellular and molecular level that shows many similarities with atherosclerosis, ranging from endothelial dysfunction to, ultimately, calcification.[9]

In rheumatic aortic stenosis, the underlying process includes progressive fibrosis of the valve leaflets with varying degrees of commissural fusion, often with retraction of the leaflet edges and, in certain cases, calcification. As a consequence, the rheumatic valve often is regurgitant and stenotic. Coexistent mitral valve disease is common.

Other, infrequent causes of aortic stenosis include obstructive vegetations, homozygous type II hypercholesterolemia, Paget disease, Fabry disease, ochronosis, and irradiation.

It is worthwhile to note that although differentiation between tricuspid and bicuspid aortic stenosis is frequently made, it is often difficult to determine the number of aortic valve leaflets. A study comparing operatively excised aortic valve structure evaluation by cardiac surgeon versus pathologist found that valve structure determination was frequently incongruous.[10]

PreviousNextEpidemiology

Severe aortic stenosis is rare in infancy, occurring in 0.33% of live births, and is due to a unicuspid or bicuspid valve. Most patients with a congenitally bicuspid aortic valve who develop symptoms do not do so until middle age or later. Patients with rheumatic aortic stenosis typically present with symptoms after the sixth decade of life.

Aortic sclerosis (aortic valve calcification without obstruction to blood flow, considered a precursor of calcific degenerative calcific aortic stenosis) increases in incidence with age and is present in 29% of individuals older than 65 years and in 37% of individuals older than 75 years. In elderly persons, the prevalence of aortic stenosis is between 2% and 9%.

Degenerative calcific aortic stenosis usually manifests in individuals older than 75 years and occurs most frequently in males.[5]

PreviousNextPrognosis

Patients with severe aortic stenosis may be asymptomatic for many years despite the presence of severe LV outflow tract obstruction (LVOTO). LVOTOs have been associated with “high heritability.” One study suggests that 20% of patients with isolated LVOTO had an affected first-degree relative with undetected bicuspid aortic valves.[11]

Asymptomatic patients, even with critical aortic stenosis, have an excellent prognosis for survival, with an expected death rate of less than 1% per year; only 4% of sudden cardiac deaths in severe aortic stenosis occur in asymptomatic patients. A new proposed aortic stenosis grading classification that integrates valve area and flow-gradient patterns has been found to allow for better characterization of the clinical outcome among patients with asymptomatic severe aortic stenosis.[12]

Although the presence of low-gradient "severe stenosis" (defined as aortic valve area 2 and mean gradient 40 mm Hg) is considered by some to be associated with a poor prognosis, the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study found that such patients have an outcome similar to that of patients with moderate stenosis.[13]

Among symptomatic patients with medically treated, moderate-to-severe aortic stenosis, mortality rates from the onset of symptoms are approximately 25% at 1 year and 50% at 2 years. More than 50% of deaths are sudden. In patients in whom the aortic valve obstruction remains unrelieved, the onset of symptoms predicts a poor outcome with medical therapy; the approximate time interval from the onset of symptoms to death is 1.5-2 years for heart failure, 3 years for syncope, and 5 years for angina.

Although the obstruction tends to progress more rapidly in degenerative calcific aortic valve disease than in congenital or rheumatic disease, predicting the rate of progression in individual patients is not possible. Catheterization and echocardiographic studies suggest that, on average, the valve area declines 0.1-0.3 cm2 per year; the systolic pressure gradient across the valve can increase by as much as 10-15 mm Hg per year. Obstruction progresses more rapidly in elderly patients with coronary artery disease and chronic renal insufficiency.

PreviousNextPatient Education

For patient education information, see eMedicineHealth's patient education article Angina Pectoris.

PreviousProceed to Clinical Presentation  Contributor Information and DisclosuresAuthor

Xiushui (Mike) Ren, MD  Cardiologist, The Permanente Medical Group; Associate Director of Research, Cardiovascular Diseases Fellowship, California Pacific Medical Center
Xiushui (Mike) Ren, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, and American Society of Echocardiography
Disclosure: Nothing to disclose.

Chief Editor

Richard A Lange, MD  Professor and Executive Vice Chairman, Department of Medicine, Director, Office of Educational Programs, University of Texas Health Science Center at San Antonio
Richard A Lange, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American Heart Association, and Association of Subspecialty Professors
Disclosure: Nothing to disclose.

Additional Contributors

Jerry Balentine, DO Professor of Emergency Medicine, New York College of Osteopathic Medicine; Executive Vice President, Chief Medical Officer, Attending Physician in Department of Emergency Medicine, St Barnabas Hospital

Jerry Balentine, DO is a member of the following medical societies: American College of Emergency Physicians, American College of Osteopathic Emergency Physicians, American College of Physician Executives, American Osteopathic Association, and New York Academy of Medicine

Disclosure: Nothing to disclose.

Edward Bessman, MD, MBA Chairman and Clinical Director, Department of Emergency Medicine, John Hopkins Bayview Medical Center; Assistant Professor, Department of Emergency Medicine, Johns Hopkins University School of Medicine

Edward Bessman, MD, MBA is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

David FM Brown, MD Associate Professor, Division of Emergency Medicine, Harvard Medical School; Vice Chair, Department of Emergency Medicine, Massachusetts General Hospital

David FM Brown, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Steven J Compton, MD, FACC, FACP, FHRS Director of Cardiac Electrophysiology, Alaska Heart Institute, Providence and Alaska Regional Hospitals

Steven J Compton, MD, FACC, FACP, FHRS is a member of the following medical societies: Alaska State Medical Association, American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, and Heart Rhythm Society

Disclosure: Nothing to disclose.

Daniel P Lombardi, DO Clinical Assistant Professor, New York College of Osteopathic Medicine; Attending Physician, Associate Department Director and Program Director, Department of Emergency Medicine, St Barnabas Hospital

Daniel P Lombardi, DO is a member of the following medical societies: American College of Emergency Physicians, American College of Osteopathic Emergency Physicians, and American Osteopathic Association

Disclosure: Nothing to disclose.

John A McPherson, MD, FACC, FAHA, FSCAI Associate Professor of Medicine, Division of Cardiovascular Medicine, Director of Cardiovascular Intensive Care Unit, Vanderbilt Heart and Vascular Institute

John A McPherson, MD, FACC, FAHA, FSCAI is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American Heart Association, Society for Cardiac Angiography and Interventions, Society of Critical Care Medicine, and Tennessee Medical Association

Disclosure: Abbott Vascular Corp. Consulting fee Consulting

Bekir H Melek, MD, FACC Assistant Professor of Clinical Medicine, Department of Medicine, Section of Cardiology, Tulane University School of Medicine

Disclosure: Nothing to disclose.

Gary Setnik, MD Chair, Department of Emergency Medicine, Mount Auburn Hospital; Assistant Professor, Division of Emergency Medicine, Harvard Medical School

Gary Setnik, MD is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, and Society for Academic Emergency Medicine

Disclosure: SironaHealth Salary Management position; South Middlesex EMS Consortium Salary Management position; ProceduresConsult.com Royalty Other

James V Talano, MD, MM, FACC Director of Cardiovascular Medicine, SWICFT Institute

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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  Calcific aortic stenosis (parasternal long-axis and short-axis views). Stenotic aortic valve (macroscopic appearance). Table 1. Common Causes of Aortic Stenosis Among Patients Requiring SurgeryTable 2. ACC/AHA Recommendations for Echocardiography (Imaging, Spectral, and Color Doppler) in Aortic StenosisTable 3. Criteria for Determining Severity of Aortic StenosisTable 4. Recommendations for Cardiac Catheterization in Aortic StenosisTable 5. Recommendations for Aortic Valve Replacement in Aortic StenosisTable 1. Common Causes of Aortic Stenosis Among Patients Requiring SurgeryAge Age >70 years (n=322) Bicuspid AV (50%)

Postinflammatory (25%)

Degenerative (18%)

Unicommissural (3%)

Hypoplastic (2%)

Indeterminate (2%)

Degenerative (48%)

Bicuspid (27%)

Postinflammatory (23%)

Hypoplastic (2%)

Table 2. ACC/AHA Recommendations for Echocardiography (Imaging, Spectral, and Color Doppler) in Aortic StenosisIndication Class Diagnosis and assessment of severity of aortic stenosisIAssessment of LV size, function, and/or hemodynamicsIReevaluation of patients with known aortic stenosis with changing symptoms or signsIAssessment of changes in hemodynamic severity and ventricular function in patients with known aortic stenosis during pregnancyIReevaluation of asymptomatic patients with severe aortic stenosisIReevaluation of asymptomatic patients with mild to moderate aortic stenosis and evidence of LV dysfunction or hypertrophyIIaRoutine reevaluation of asymptomatic adult patients with mild aortic stenosis who have stable physical signs and normal LV size and function IIITable 3. Criteria for Determining Severity of Aortic StenosisSeverity Mean gradient (mm Hg) Aortic valve area (cm2) Mild>1.5Moderate25-401-1.5Severe>40
(or 2/m2 body surface area)

Critical>80Table 4. Recommendations for Cardiac Catheterization in Aortic StenosisIndication Class Coronary angiography before aortic valve replacement in patients at risk for coronary artery diseaseIAssessment of severity of aortic stenosis in symptomatic patients when aortic valve replacement is planned or when noninvasive tests are inconclusive or a discrepancy exists in the clinical findings regarding the severity of aortic stenosis or the need for surgery ICoronary angiography before aortic valve replacement in patients for whom a pulmonary autograft (Ross procedure) is contemplated and the origin of the coronary arteries was not identified by noninvasive tests IWith infusion of dobutamine, can be useful for evaluation of patients with low-flow/low-gradient aortic stenosis and LV dysfunctionIIaNot recommended for hemodynamic measurements for assessment of aortic stenosis severity when noninvasive techniques are adequate and concord with clinical findings IIINot recommended for hemodynamic measurements for assessment of LV function and aortic stenosis severity in asymptomatic patientsIIITable 5. Recommendations for Aortic Valve Replacement in Aortic StenosisIndication Class Symptomatic patients with severe aortic stenosisIPatients with severe aortic stenosis undergoing coronary artery bypass surgeryIPatients with severe aortic stenosis undergoing surgery on the aorta or other heart valvesIPatients with severe aortic stenosis and LV systolic dysfunction (ejection fraction IPatients with moderate aortic stenosis undergoing coronary artery bypass surgery or surgery on the aorta or other heart valvesIIaPatients with mild aortic stenosis undergoing coronary artery bypass surgery when there is evidence that progression may be rapid, such as moderate-to-severe valve calcificationIIbAsymptomatic patients with severe aortic stenosis and abnormal response to exercise (eg, hypotension)IIbAsymptomatic patients with severe aortic stenosis and a high likelihood of rapid progression (based on age, calcification, and coronary artery disease) or if surgery might be delayed at the time of symptom onsetIIbAsymptomatic patients with extremely severe aortic stenosis (valve area less than 0.6 cm2, mean gradient greater than 60 mm Hg, and jet velocity greater than 5 m per second) if the patient’s expected operative mortality is 1% or lessIIbAVR is not useful for prevention of sudden death in asymptomatic patients with none of the findings listed under asymptomatic patients with severe aortic stenosisIII View Table List  Read more about Aortic Stenosis on MedscapeRelated Reference Topics
Aortic Stenosis Pathology
Pediatric Supravalvar Aortic Stenosis
Pediatric Valvar Aortic Stenosis
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Medscape Reference © 2011 WebMD, LLC, Aortic Stenosis

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Carotid Artery Dissection

Background

Carotid artery dissection begins as a tear in one of the carotid arteries of the neck, which allows blood under arterial pressure to enter the wall of the artery and split its layers. The result is either an intramural hematoma or an aneurysmal dilatation, either of which can be a source of microemboli, with the latter also causing a mass effect on surrounding structures.

Carotid artery dissection is a significant cause of ischemic stroke in all age groups, but it occurs most frequently in the fifth decade of life and accounts for a much larger percentage of strokes in young patients.[1] Dissection of the internal carotid artery can occur intracranially or extracranially, with the latter being more frequent. Internal carotid artery dissection can be caused by major or minor trauma, or it can be spontaneous, in which case, genetic, familial, or heritable disorders are likely etiologies.

Although in practice, dissections are labeled spontaneous in the absence of major blunt or penetrating trauma,[2] when they are associated with minor mechanism trauma they may be caused or influenced by an underlying arteriopathy.[3] Patients can present in a variety of settings, such as a trauma bay with multiple traumatic injuries; a physician’s office with nonspecific head, neck, or face pain; or an emergency department (ED) with a partial Horner syndrome.

Sophisticated imaging techniques, which have improved over the past 2 decades, are required to confirm the presence of dissection. Most ischemic cerebral symptoms arise from thromboembolic events; therefore, early institution of antithrombotic treatment provides the best outcome.[4]

Once diagnosed and treated, patients with carotid artery dissection require regular follow-up and imaging studies of both carotid arteries because healing usually takes 3-6 months and the incidence of contralateral dissection is higher than in the general population. When the condition is diagnosed early, the prognosis is usually good. A high index of suspicion is required to make this difficult diagnosis.

For patient education resources, see the Stroke Center, as well as Worst Headache of Your Life, Transient Ischemic Attack (Mini-stroke), and Stroke.

NextPathophysiology

Although the cause of internal carotid artery dissection remains elusive, mechanical forces (eg, trauma, blunt injury, and stretching) and underlying arteriopathies (eg, Ehlers-Danlos syndrome IV and other connective tissue disorders and aberrations), either alone or in combination, account for most of the pathophysiology. It is widely accepted that carotid artery dissection is a multifactorial disease.[5]

Carotid artery dissection begins as a tear in the tunica intima or directly within the tunica media (possibly originating from the vasa vasorum).[1] The blood dissects along the artery to create an intramural hematoma that leads to a thrombus, which can narrow the carotid artery lumen and become a nidus for distal embolization (see the image below).[2]

Arterial dissection. (A) Tear and elevation of intima from wall of artery, resulting in luminal stenosis. Illustration shows stasis of flow in false lumen beneath elevated intima. This condition creates blind pouch that predisposes patient to thrombus formation. (B) Subadventitial dissection represents hemorrhage between media and adventitia. Artery may become dilated as result of thickening of arterial wall, with some degree of luminal narrowing. Elevation of intimal flap is not commonly associated with this type of dissection. Hemorrhage may extravasate through adventitia, resulting in pseudoaneurysm or fistula formation.

Sometimes, the dissection plane lies between the tunica media and the tunica adventitia, resulting in an aneurysmal outpouching of the arterial wall that may also become a source of distal emboli. Aneurysmal dilatation can also cause a mass effect on nearby structures such as sympathetic fibers and the lower cranial nerves.[1, 2] The dilatation resulting from an internal carotid artery dissection may be termed a true rather than a false aneurysm because the wall is composed of blood vessel elements.

PreviousNextEtiology

Causes of carotid artery dissection include the following:

Heritable connective-tissue disordersEhlers-Danlos syndrome type IVFibromuscular dysplasiaCystic medial necrosisMarfan syndromeAutosomal dominant polycystic kidney diseaseOsteogenesis imperfecta type IOral contraceptivesHypertensionNeck manipulation or strain - This can result from intentional manipulation or from other strain that may occur during sports activities, yoga, or even apparently minimal activity (eg, overhead painting) Blunt trauma from high impact and seemingly minor mechanisms of injuryPenetrating traumaWearing a 3-point restraint seat belt during a motor vehicle crashSmokingRespiratory tract infectionPreviousNextEpidemiology

The annual incidence of symptomatic spontaneous internal carotid artery dissection is 2.5-3 per 100,000.[1] The incidence of carotid artery dissection as a result of blunt injuries (mainly high-speed motor vehicle accidents) ranges from less than 1% to 3%.[6] The actual incidence may be higher; some dissections are asymptomatic or cause only minor transient symptoms and remain undiagnosed.

Age- and sex-related demographics

Internal carotid artery dissection is a common cause of ischemic stroke in patients younger than 50 years and accounts for as many as 25% of ischemic strokes in young and middle-aged patients.[1] The mean age for ischemic stroke secondary to internal carotid artery dissection from blunt traumatic injury is even younger: 35-38 years. Dissection of the intracranial part of the internal carotid artery is rare at any age, because the intracranial carotid artery is less mobile and the skull absorbs most of the force of trauma.

No significant gender-based difference in frequency exists for spontaneous internal carotid artery dissection, though there may be a slight male preponderance when traumatic causes of carotid artery dissection are taken into account.

PreviousNextPrognosis

In general, the prognosis depends on the severity of the initial ischemic injury and the extent of collateral circulation. Overall, the prognosis for spontaneous internal carotid artery dissection is favorable, with about 75% of patients making a good recovery.[1, 7] The reported mortality is less than 5%. Patients who have a dissection secondary to trauma have a much higher rate of mortality on discharge.

Morbidity from carotid artery dissection ranges in severity from transient focal deficits to permanent cerebral or retinal ischemic injury. More than one half of patients with spontaneous carotid artery dissection develop stroke,[1] although this may be delayed by hours or days. Rates of delayed stroke due to blunt-traumatic causes of carotid artery injury range from 3% in grade I injuries to 44% in grade IV injuries.[2]

In the setting of blunt trauma, 37-58% of patients have permanent neurologic deficits on discharge,[6] though early use of antithrombotic therapy has essentially eliminated ischemic events in asymptomatic patients with carotid artery dissection.[4, 8]

As in other causes of stroke in young adults, the functional outcome is generally good, and recurrence of cerebral ischemia and carotid artery dissection is rare.[5] The risk of recurrence is highest in the first month and then remains in the area of 1% per year for about a decade. Headache may persist, in some cases for years after the dissection.

PreviousProceed to Clinical Presentation , Carotid Artery Dissection

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Loeffler Endocarditis

Background

Loeffler endocarditis and endomyocardial fibrosis are restrictive cardiomyopathies, defined as diseases of the heart muscle that result in impaired ventricular filling with normal or decreased diastolic volume of either or both ventricles. Systolic function and wall thickness may remain normal, especially early in the disease, as reported by Richardson and associates.[1, 2] Both conditions are associated with eosinophilia.

The associations among eosinophilia, active carditis, and multiorgan involvement were first described by Loeffler in 1936.[3] Pathologic specimens in Loeffler endocarditis show eosinophilic myocarditis, a tendency toward endomyocardial fibrosis and clinical manifestations of thromboembolism, and acute heart failure.

Eosinophilic states that may occur in association with Loeffler endocarditis include hypereosinophilic syndrome, eosinophilic leukemia, carcinoma, lymphoma, drug reactions or parasites, as reported in multiple case series.

Although eosinophilic endocardial disease has been well described, myocardial and vascular damage due to eosinophilic infiltration and degranulation is rarely diagnosed during life, as reported by Oakley et al and others.[4] Herzog et al and Tonnesen et al have proposed that the reason for this situation may be the rapidly fatal evolution of most cases of eosinophilic arteritis and myocarditis.[5, 6] These conditions are usually diagnosed based on postmortem examination and nonspecificity of clinical manifestations, as reported by Kim et al, Isaka et al, and Seshadri et al.[7, 8, 9]

Pathophysiologically, the fibrotic stage of Loeffler endocarditis is very similar to the disease entity described as endomyocardial fibrosis, which is indolent in comparison to Loeffler endocarditis. The tropical form of endomyocardial fibrosis is associated with eosinophilia, a common finding in Loeffler endocarditis.

NextPathophysiology

Endomyocardial damage in Loeffler endocarditis is well known and described in a study by Solley and associates.[10] Myocardial involvement is less well known and has been considered a manifestation of an acute necrotic stage of eosinophilic endomyocardial disease, as reported by Olsen and colleagues.[11] More recently, cases of isolated eosinophilic myocarditis have been reported without signs of endomyocardial involvement, with or without vasculitis.

Additionally, idiopathic eosinophilic endomyocarditis, in the absence of peripheral eosinophilia, has been reported by Priglinger et al.[12]

Morphologic abnormalities of eosinophils have been noted in patients with Loeffler endocarditis, suggesting that these eosinophils were mature or stimulated. The intracytoplasmic granular content of activated eosinophils is thought to be responsible for the toxic damage to the heart, as reported by Tai and associates.[13] Spry et al reported eosinophilic degranulation of basic proteins causing myocardial damage in tissue cultures in vitro.[14] Gliech et al reported a dose-dependent cytotoxic effect of the eosinophilic granular proteins, inhibiting multiple enzyme systems.[15]

The cationic eosinophilic proteins bind to the anionic endothelial protein, thrombomodulin. This complex impairs anticoagulant activities, leading to enhanced endocardial thrombus formation, as reported by Slungaard and colleagues.[16]

Toxins released by the eosinophils include eosinophil-derived neurotoxin, cationic protein, major basic protein, reactive oxygen species, and arachidonic acid derivatives. As described by Cunningham et al, these toxins may cause endothelial and myocyte damage, resulting in thrombosis, fibrosis, and infarction.[17]

The intensity and timing of the active carditis is related closely to the severity of the circulating eosinophilia. Some have suggested that, particularly in the tropics, patients who present with later fibrotic stages of endomyocardial disease may have had either transient earlier bouts of moderate eosinophilia with spontaneous resolution, or only moderate levels of eosinophilia leading to a low-grade endomyocarditis with gradual progressive fibrosis, as reported by Olsen et al.[11]

Molecular pathophysiology

Cools et al reported a landmark finding by treating patients with hypereosinophilic syndrome (HES) with imatinib, a tyrosine kinase inhibitor.[18]

The gene defect is localized to an interstitial chromosomal deletion on chromosome band 4q12, resulting in fusion of the Fip1-like1 (FIP1L1) gene to the platelet-derived growth factor gene alpha (PDGFRA). The protein product of this gene is a tyrosine kinase enzyme that transforms the hematopoietic stem cells. This FIP1L1-PDGFRA fusion gene defect was identified in 9 of 16 patients treated with imatinib. This study also highlights the importance of reclassifying HES as a myeloproliferative disorder of a possible single clone based on genotyping, as the FIP1L1-PDGFRA gene rearrangement is a clonal abnormality. Treatment with imatinib caused rapid regression of eosinophilic proliferation and endomyocardiopathy in subsequent cases reported by Vandenberghe et al and Rotoli et al.[19, 20]

The following list summarizes the initial clinical presentations of eosinophilic endomyocardial disease in relation to the predominant pathologic stage of the disease as reported by Alderman et al in the Textbook of Cardiovascular Medicine.[21] Death is usually related to multiorgan dysfunction in the presence of congestive heart failure. (See Medscape's Heart Failure Resource Center.)

The initial clinical presentation and stages of eosinophilic endomyocardial disease are as follows:[21]

Necrotic stage (early stage) Hypereosinophilia with systemic illness (20-30%) FeverSweatingChest pain (as described by Bestetti et al[22] ) LymphadenopathySplenomegalyAcute carditis (20-50%) AnorexiaWeight lossCoughPulmonary infiltratesSkin and retinal lesionAtrioventricular valve (AV) valve regurgitationBiventricular failurePolymorphic ventricular tachycardia[23] Thrombotic stage Thrombotic emboli (10-20%) Cerebral, splenic, renal, and coronary infarctionSplinter hemorrhagesFibrotic stage (late stage) Restrictive myopathy (10%) AV valvular regurgitationRight and left heart failure

The image shows dense fibrosis of ventricle in a postmortem dissected heart.

Myocardial as well as valvular involvement with Loffler endocarditis. This image shows dense fibrosis of ventricle in a postmortem dissected heart. PreviousNextEpidemiologyFrequencyUnited States

The condition is rare and is seen mostly in immigrants from Africa, Asia, and South America.

International

Loeffler endocarditis is primarily confined to the rain forest (tropical and temperate) belts of Africa, Asia, and South America.

Mortality/Morbidity

The literature reports a 35-50% 2-year mortality rate in patients with advanced myocardial fibrosis. Substantially better survival rates may be seen in less symptomatic patients who have milder forms of the disease. As noted, this rate may reflect underdiagnosis of clinically inapparent disease, as for other types of cardiomyopathy.

Race

The condition has a predilection for African and African American populations, notably the Rwanda tribe in Uganda, and for people of low socioeconomic status. Whether this is due to genetic factors or the epidemiology of underlying environmental factors is not known.

Sex

Loeffler endocarditis has a predilection for males. However, endomyocardial fibrosis, which has similar clinical manifestations, is found equally frequently in both sexes.

Age

The reported age range is 4-70 years. Loeffler endocarditis particularly affects young males, as does its close counterpart, endomyocardial fibrosis, which is more common in children and young adults.

PreviousProceed to Clinical Presentation , Loeffler Endocarditis

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Mitral Stenosis

Background

Mitral stenosis (MS) is characterized by obstruction to left ventricular inflow at the level of mitral valve due to structural abnormality of the mitral valve apparatus. The most common cause of mitral stenosis is rheumatic fever. Other less common etiologies include congenital mitral stenosis, malignant carcinoid disease, systemic lupus erythematosus, rheumatoid arthritis, mucopolysaccharidoses of the Hunter-Hurler phenotype, Fabry disease, Whipple disease, and methysergide therapy. The association of atrial septal defect with rheumatic mitral stenosis is called Lutembacher syndrome.

A number of conditions can simulate the physiology of mitral stenosis: severe nonrheumatic mitral annular calcification, infective endocarditis with large vegetation, left atrial myxoma, ball valve thrombus, or cor triatriatum.

Stenosis of the mitral valve typically occurs decades after the episode of acute rheumatic carditis. Acute insult leads to formation of multiple inflammatory foci (Aschoff bodies, perivascular mononuclear infiltrate) in the endocardium and myocardium. Small vegetations along the border of the valves may also be observed. With time, the valve apparatus becomes thickened, calcified, and contracted, and commissural adhesion occurs, ultimately resulting in stenosis.

Whether the progression of valve damage is due to hemodynamic injury of the already affected valve apparatus or to the chronic inflammatory nature of the rheumatic process is unclear.

NextPathophysiology

The normal mitral valve orifice area is approximately 4-6 cm2. As the orifice size decreases, the pressure gradient across the mitral valve increases to maintain adequate flow.

Patients will not experience valve-related symptoms until the valve area is 2-2.5 cm2 or less, at which point moderate exercise or tachycardia may result in exertional dyspnea from the increased transmitral gradient and left atrial pressure.

Severe mitral stenosis occurs with a valve area of less than 1 cm2. As the valve progressively narrows, the resting diastolic mitral valve gradient, and hence left atrial pressure, increases. This leads to transudation of fluid into the lung interstitium and dyspnea at rest or with minimal exertion. Hemoptysis may occur if the bronchial veins rupture and left atrial dilatation increases the risk for atrial fibrillation and subsequent thromboembolism.

Pulmonary hypertension may develop as a result of (1) retrograde transmission of left atrial pressure, (2) pulmonary arteriolar constriction, (3) interstitial edema, or (4) obliterative changes in the pulmonary vascular bed (intimal hyperplasia and medial hypertrophy). As pulmonary arterial pressure increases, right ventricular dilation and tricuspid regurgitation may develop, leading to elevated jugular venous pressure, liver congestion, ascites, and pedal edema.

Left ventricular end-diastolic pressure and cardiac output are usually normal in the person with isolated mitral stenosis. As the severity of stenosis increases, the cardiac output becomes subnormal at rest and fails to increase during exercise. Approximately one third of patients with rheumatic mitral stenosis have depressed left ventricular systolic function as a result of chronic rheumatic myocarditis. The presence of concomitant mitral regurgitation, systemic hypertension, aortic stenosis, or myocardial infarction can also adversely affect left ventricular function and cardiac output.

PreviousNextEpidemiologyFrequencyUnited States

The prevalence of rheumatic disease in developed nations is steadily declining with an estimated incidence of 1 in 100,000.

International

The prevalence of rheumatic disease is higher in developing nations than in the United States.[1] In India, for example, the prevalence is approximately 100-150 cases per 100,000, and in Africa the prevalence is 35 cases per 100,000.

Mortality/Morbidity

Mitral stenosis is a progressive disease consisting of a slow, stable course in the early years followed by an accelerated course later in life. Typically, there is a latent period of 20-40 years from the occurrence of rheumatic fever to the onset of symptoms. Once symptoms develop, it is almost a decade before they become disabling. In some geographic areas, mitral stenosis progresses more rapidly, presumably due to either a more severe rheumatic insult or repeated episodes of rheumatic carditis due to new streptococcal infections, which results in severe symptomatic mitral stenosis in the late teens and early 20s.

In the asymptomatic or minimally symptomatic patient, survival is greater than 80% at 10 years. When limiting symptoms occur, 10-year survival is less than 15% in the patient with untreated mitral stenosis. When severe pulmonary hypertension develops, mean survival is less than 3 years. Most (60%) patients with severe untreated mitral stenosis die of progressive pulmonary or systemic congestion, but others may suffer systemic embolism (20-30%), pulmonary embolism (10%), or infection (1-5%).

Sex

Two thirds of all patients with rheumatic mitral stenosis are female.

Age

The onset of symptoms usually occurs between the third and fourth decade of life.

PreviousProceed to Clinical Presentation , Mitral Stenosis

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Pulmonic Valvular Stenosis

Background

Pulmonic valvular stenosis (PVS) is described as lesions that collectively are associated with obstruction to the right ventricular outflow tract. Stenosis may be valvular, subvalvular, or supravalvular. Isolated pulmonary stenosis is considered to be a rare congenital abnormality.[1] It is the most common cause of congenital outflow tract obstruction, resulting in decreased flow from the right ventricle to the pulmonary arteries.[2] Isolated right ventricular outflow tract obstruction is pulmonic valvular stenosis in 80% of cases.[3]

Pulmonic valvular disease is clinically detected at different stages of life. The more severe the obstruction, the earlier the valvular abnormality is detected. Pulmonic valvular stenosis is most often associated with the failure of the valvular leaflets to fuse and less commonly is caused by dysplastic thickening of the valves.[4]

Neonates with critical stenosis typically present with central cyanosis at birth. Infants and children with ejection murmurs auscultated in the pulmonic area are often evaluated, and stenosis is discovered during this period. Symptoms of pulmonic stenosis have been observed to progress with time.[5] Adults present with symptoms of congestive heart failure (CHF) and right ventricular outflow obstruction that is progressive in nature.[6] Many of these congenital valvular malformations occur in the setting of well-defined syndromes. Examples of such syndromes involving stenosis of the pulmonic valves are Holt-Oram syndrome, Noonan syndrome, and Leopard syndrome.[5, 7] Eisenmenger syndrome associated with trisomy 13 also results in pulmonary outflow tract obstruction; however, often, other cardiac malformations are involved as well.[8]

A large study called the Second Natural History Study of Congenital Heart Defects analyzed the treatment, quality of life, echocardiography findings, complications, exercise responses, and predisposition to endocarditis with regards to cardiac valvular disease, and pulmonary stenosis was found to be the most benign valvular lesion.[9]

NextPathophysiology

Supravalvular, valvular, and subvalvular lesions are associated with pulmonic valvular stenosis. Lesions vary in severity, from with simple valvular hypertrophy to complete outflow obstruction and atresia.[6] The trileaflet pulmonic valve ranges from thickened or partially fused commissures to an imperforate valve.

Most cases of pulmonic valvular stenosis are congenital. Often times, the valvular abnormality is associated with syndromes such as Noonan syndrome and Leopard syndrome. The inheritance pattern of pulmonic valvular stenosis is poorly understood, although these syndromes display an autosomal dominant pattern. Rarely, pulmonic stenosis is associated with recessively transmitted conditions such as Laurence-Moon-Biedl syndrome. Mutations in germlines PTPN1 and RAF1 have been associated with these valvular abnormalities.[10] Supravalvular lesion may occur in the setting of tetralogy of Fallot, Williams syndrome, Alagille syndrome, as well as Noonan syndrome.[6]

The myocardial cushion begins as a matrix of endothelial cells and an outer mitochondrial layer separated by cardiac jelly. After endocardial cushion formation, the endothelial mesenchymal transformation (EMT), which are specified endothelial cells, differentiate and migrate into the cardiac jelly. Through a poorly understood process, the cardiac jelly goes through local expansion and bolus swelling, and cardiac valves are formed. The aortic and pulmonic valves develop from the outflow tract of the endocardial cushion, also believed to have neural crest cell migration from the brachial crest during development.[5]

Research suggests that the vascular endothelial growth factor (VEGF), a pleiotropic factor, is responsible for signaling the development of the endocardial cushion. Hypoxia and glucose have regulatory effects on this factor. Infants born to hyperglycemic mothers have a 3-fold increase in cardiovascular abnormalities. There has been correlation between intrapartum hypoxic events and valvular disease. Additionally, numerous signaling molecules contribute to VEGF and EMT such as the ERB-B signaling in the cardiac jelly, transforming growth factor (TGF)/cadherin, and BMP/TGF-beta.[5]

The pulmonic valve develops between the 6th and 9th week of gestation. Normally, the pulmonic valve is formed from 3 swellings of subendocardial tissue called the semilunar valves. These tubercles develop around the orifice of the pulmonary tree. The swellings are normally hollowed out and reshaped to form the 3 thin-walled cusps of the pulmonary valve. In Noonan syndrome, tissue pad overgrowth within the sinuses interferes with the normal mobility and function of the valve.

Failure to develop normally can result in the following malformations: fusion of 2 of the cusps, 3 leaflets that are thickened and partially fused at the commissures, or a single cone-shaped valve.

In the congenital rubella syndrome, supravalvular pulmonic and pulmonary artery branch stenoses are frequently present. Acquired valvular disease is rare. The most common etiologies are carcinoid syndrome, rheumatic fever, and homograft dysfunction.[4]

Years of stenosis can result in subendocardial hypertrophy causing significant outflow obstruction and resulting in right ventricular pressure overload and pulmonary hypertension. As this process worsens, the asymptomatic adult becomes gradually symptomatic.[11, 12]

PreviousNextEpidemiologyFrequencyUnited States

Approximately 5 out of 1000 infants are born with a congenital cardiac malformation.[5] Cardiac malformation is the most common congenital abnormality. Among cardiac malformations, valvular defects are the most common subtype, accounting for 25% of all malformations involving the myocardium.[5] Prevalence of pulmonary stenosis is 8-12% of all congenital heart defects.

Isolated pulmonic valvular stenosis with intact ventricular septum is the second most common congenital cardiac defect. Pulmonic valvular stenosis may occur in as many as 30% of all patients who have other congenital heart defects.

Sixty percent of patients with Noonan syndrome are found to have some degree of pulmonic valvular stenosis.[7]

Mortality/Morbidity

Valvular disease in general has high morbidity and mortality rates. Isolated pulmonic valvular disease has been found to be the most benign.[9] In the United States, about 82,000 valvular replacements are performed per year.[5] Survival to adulthood is most common, as symptoms and extent of disease progress with time.[2]

Much of what is known about the morbidity and mortality of pulmonic valvular stenosis comes from the Natural History Study of Congenital Heart Defects and the Second Natural History Study of Congenital Heart Defects. The Natural History Study of Congenital Heart Defects included an initial cardiac catheterization and then follow up for events over an 8-year period. The Second Natural History Study of Congenital Heart Defects reported on 16-27 years of follow up from the same cohort.[9]

The studies demonstrated that adverse outcomes directly relate to the right ventricular systolic pressure gradient.[13] Mild pulmonic valvular stenosis with pressure gradient across the valve less than 50 mm Hg was found to be well tolerated clinically and subjectively.[9] Of these patients, 94% were asymptomatic, without cyanosis or congestive heart failure.[14, 15] Moderate-to-severe pulmonic valvular stenosis, with pressure gradient greater than 50 mm Hg is more often associated with decreased cardiac output, right ventricular hypertrophy, early congestive heart failure (CHF), and cyanosis. Valvulotomy has been shown to improve morbidity and mortality and is indicated with these gradients.[9]

The morbidity and mortality of valvular lesions in regards to pregnancy and fetal outcomes has not been rigorously studied. A case-control study of 17 patients suggested that there is no adverse impact on either the mother or the fetus.[16]

Sex

The male-to-female ratio of pulmonic valvular stenosis is approximately 1:1.

Age

Pulmonic valvular stenosis most commonly presents in newborns. It can be asymptomatic for years.

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