Bedside Ultrasonography in Deep Vein Thrombosis

OverviewIntroduction

Venous thrombosis is a major cause of morbidity and mortality in the United States and a frequent cause of presentation in many emergency departments (EDs). The sequelae of deep vein thromboses (DVTs) range from the more common chronic venous stasis to the most serious pulmonary emboli (PEs).[1] PEs have been described as one of the most common preventable causes of death, and approximately two thirds of PEs are estimated to originate in the lower extremities as DVTs. The rate of propagation from DVT to PE is estimated to range from 10-50%.[2, 3, 4] Treatments with anticoagulation or Greenfield filter placement are extremely effective if used early, thereby underscoring the need for rapid diagnosis.

Compression ultrasonography has proven to be a highly sensitive and specific modality for the recognition of lower extremity DVTs without the need for radiation or contrast exposure.[5, 6] Traditional lower extremity studies interrogate and review the entire lower extremity vasculature, are performed by an ultrasonography technologist, and are read by a radiologist.[7, 8] However, these factors are not always available and have been shown to delay the time to diagnosis and potential treatment of a DVT by up to 2 hours.[9, 10]

To detect proximal lower-extremity DVTS, EDs now use a modified 2-point compression technique that focuses on the highest probability areas, decreases the study time to less than 5 minutes, and provides similar sensitivity and specificity.[11, 12, 13] In patients with a clinically suspected DVT, a negative compression ultrasound study may safely delay the need for anticoagulation therapy.[14] The 2-point DVT compression examination has been assessed in multiple randomized controlled studies and is well accepted when used properly with pretest probability assessments.[11, 15, 16]

The safety, ease of use, rapid time to diagnosis, low cost, and accessibility make bedside ultrasonography for DVT especially useful for emergency and critical care clinicians.

Indications

Patients who have risk factors for DVT or pulmonary embolism (PE), and in whom a clinician suspects DVT or PE, should have workups that include, but are not necessarily limited to, bedside compression ultrasonography.

Contraindications

No absolute contraindications to bedside ultrasonography for DVT exist.

If the clinical suspicion and pretest probability for a PE are high enough that a spiral computed tomography (CT) scan with intravenous contrast or V/Q (ventilation/perfusion) scan is warranted, then ultrasonography should not delay such studies or any further treatment goals. Additionally, thrombus in the pelvic veins will not be detected with this technique and, although rare, may be best evaluated with CT or magnetic resonance (MR) venography.[17]

NextPreparationEquipment

The following equipment is indicated:

Portable bedside ultrasound machine with a high-resolution linear transducerUltrasound gelPositioning

The patient should be supine with the leg in question exposed up to the inguinal ligament. Bedside ultrasonography for deep vein thrombosis (DVT) is performed in 2 principal positions, one for each area of examination. The images below depict ideal positions. Patient status and cooperation, however, ultimately determine what kind of positioning is possible. Ideally, 30-40 degrees of reverse Trendelenburg facilitates the examination by increasing venous distention.

When examining the femoral vein, the patient should be supine with the hip externally rotated and flexed, as shown below.

Patient positioning when assessing the femoral vein.

When examining the popliteal vein, the patient needs to expose the popliteal fossa on the posteromedial aspect of the knee. The patient can either dangle the leg off the edge of the bed or bend the knee and externally rotate the hip, as shown below. If necessary, the patient can also be rolled onto his or her side or into the prone position.

Patient positioning when assessing the popliteal vein. PreviousNextTechniqueOverview

Set up the portable ultrasound machine at the patient's bedside, with the linear transducer set at a frequency of 5.0-7.0 MHz. Expose the patient’s entire leg.

By convention, clinicians in EDs scan in an abdominal orientation with the probe marker pointed toward the patient’s head or right side. During the bedside ultrasonographic examination for deep vein thrombosis (DVT), the technician maintains this convention; that is, the probe marker points toward the patient’s right. In terms of orientation, remember that the top of the viewing screen is always where the transducer is touching the patient. Vascular anatomy is shown in the image below.

Lower extremity vascular anatomy.

The video below demonstrates ultrasonographic evaluation for DVT.

Demonstration of leg evaluation for deep vein thrombosis (DVT). Video courtesy of Meghan Kelly Herbst, MD. Also courtesy of Yale School of Medicine, Emergency Medicine. Femoral Vein

Position the patient as noted previously for examination of the femoral vessels (see Positioning, above). The study begins with an examination of the common femoral vein just distal to the inguinal ligament. The femoral vessels are located just inferior to the inguinal ligament and approximately midway between the pubic symphysis and the anterior superior iliac spine. The femoral artery is usually palpable. This is the initial point of examination.

Apply gel to the transducer, the patient’s leg, or both, and position the transducer transversely, just distal to the inguinal ligament, as shown below. Remember, the indicator on the probe should point toward the patient’s right. In this transverse view, the vein is imaged in cross-section.

Probe positioning for assessment of the femoral vein.

Drag or fan the transducer in a cephalad or caudad direction until the junction of the common femoral vein and the greater saphenous vein can be visualized, as shown below. The common femoral artery is lateral to the common femoral vein.

Ultrasonographic image of femoral vessels without compression.

Using the transducer, apply direct pressure to completely compress the vein. If the vein compresses completely, then a DVT at this site can be ruled out.

Be sure that enough pressure is being applied and being applied evenly. Apply enough pressure so that slight deformation of the artery is noticeable. If the vein is still not completely compressible, a DVT is present. See the image below.

Ultrasonographic image of femoral vessels with compression.

Complete compression of the vein rules out a DVT, whereas the inability to completely compress the vein rules in a DVT. Thus, compressibility is the rule in/rule out criterion for DVT on ultrasound. (See Results, below, for more details.)

Compressibility must be present in both the femoral veins and the popliteal vein. Sometimes, the angle of the transducer may need to be adjusted in order to completely compress the vein. The greater saphenous vein is a superficial vein. A clot in the greater saphenous vein near its junction with the common femoral vein, however, can easily propagate.

The examination of the common femoral vein should extend from 2 cm proximal to 2 cm distal to the intersection of the common femoral and greater saphenous veins. Distal to the greater saphenous vein, the common femoral vein splits into the deep and superficial femoral veins.

Despite its name, the superficial femoral vein is indeed a deep vein. Once collapse of both the deep and superficial femoral veins is confirmed, the examination may move on to the popliteal vein.

Popliteal Vein

Position the patient as noted earlier for examination of the popliteal vessels. (See Positioning, above.)

Again, apply gel to the transducer, the patient’s leg, or both, and position the transducer transversely in the popliteal fossa, with the probe marker directed toward the patient’s right, as shown below.

Probe positioning for assessment of the popliteal vein.

Drag or fan the transducer in a cephalad or caudad direction until the superficial popliteal artery and vein are visible, as shown below. The popliteal vein is usually posterior to the popliteal artery. Given the posterior approach of the probe (transducer face is placed in the popliteal fossa), however, the vein appears more superficial (closer to the transducer face) than the artery. The popliteal vessels are compressed more easily, so reducing probe pressure may help visualize the veins.

Ultrasonographic image of popliteal vessels with clot.

The examination should include the distal 2 cm of the popliteal vein and the proximal aspects of its trifurcation into the anterior tibial vein, the posterior tibial vein, and the peroneal vein. Anatomic variability is not uncommon, and the popliteal vein is often seen dividing into the anterior and posterior tibial veins, with the peroneal vein then splitting off from the posterior tibial vein.

Doppler Ultrasonography

Although not a formal component of the focused lower extremity compression examination for DVT, Doppler ultrasonography may be useful to help determine anatomic orientation and to further interrogate potentially misleading structures. Information obtained from Doppler ultrasonography alone, however, does not yield definitive evidence regarding clot presence.

Doppler examination assesses the direction, velocity, and pattern of blood flow, with venous and arterial vessels demonstrating characteristic patterns. Normal venous vasculature should show venous flow at baseline, augmentation of flow with calf compression, and phasic respiratory ventilation with increased flow during expiration. In general, augmentation helps to assess for obstruction distal to the probe, whereas respiratory variation helps to assess for obstruction proximal to the probe (ie, iliac veins and inferior vena cava).

Some points to keep in mind include the following:

Vessel filling defects may indicate on-site or upstream flow obstructionCysts or other fluid cavities are devoid of flowLymph nodes demonstrate dense, high vascularityPreviousNext, Bedside Ultrasonography in Deep Vein Thrombosis

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Aortitis

Background

Aortitis is literally inflammation of the aorta, and it is representative of a cluster of large-vessel diseases that have various or unknown etiologies. While inflammation can occur in response to any injury, including trauma, the most common known causes are infections or connective tissue disorders. Infections can trigger a noninfectious vasculitis by generating immune complexes or by cross-reactivity. The etiology is important because immunosuppressive therapy, the main treatment for vasculitis, could aggravate an active infectious process.

Inflammation of the aorta can cause aortic dilation, resulting in aortic insufficiency. Also, it can cause fibrous thickening and ostial stenosis of major branches, resulting in reduced or absent pulses, low blood pressure in the arms, possibly with central hypertension due to renal artery stenosis. Depending on what other vessels are involved, ocular disturbances, neurological deficits, claudication, and other manifestations of vascular impairment may accompany this disorder. See the image below.

Presence of associated morbidity in Takayasu arteritis in the United States (adapted from combined reports by Maksimowicz-McKinnon et al and Kerr).

Agents known to infect the aorta include Neisseria (eg, gonorrhea), tuberculosis, Rickettsia (eg, Rocky Mountain spotted fever) species, spirochetes (eg, syphilis), fungi (eg, aspergillosis, mucormycosis), and viruses (eg, herpes, varicella-zoster, hepatitis B, hepatitis C).

Immune disorders affecting the aorta include Takayasu arteritis, giant cell arteritis, polyarteritis nodosa, Behcet disease, Cogan syndrome, sarcoidosis, spondyloarthropathy, serum sickness, cryoglobulinemia, systemic lupus erythematosus (SLE), rheumatoid arthritis, Henoch-Schönlein purpura, and postinfectious or drug-induced immune complex disease.

Also, anti-neutrophil cytoplasmic autoantibody (ANCA) can affect the large vessels, as in Wegener granulomatosis, polyangiitis, and Churg-Strauss syndrome. Other antibodies such as anti-glomerular basement membrane (ie, Goodpasture syndrome) and anti-endothelial (ie, Kawasaki disease) also can be culprits. Transplant rejection, inflammatory bowel diseases, and paraneoplastic vasculitis also may afflict the large vessels.

The cause or causes of giant cell or temporal arteritis, Takayasu arteritis, and polyarteritis nodosa are unknown.

NextPathophysiology

The disease has 3 phases. Phase I is the prepulseless inflammatory period characterized by nonspecific systemic symptoms including low-grade fever, fatigue, arthralgia, and weight loss. Phase II involves vascular inflammation associated with pain (eg, carotidynia) and tenderness over the arteries. Phase III is the fibrosis stage, with predominant ischemic symptoms and signs secondary to dilation, narrowing, or occlusion of the proximal or distal branches of the aorta. Bruits frequently are heard, especially over carotid arteries and the abdominal aorta. The extremities become cool, and pain develops with use (ie, arm or leg claudication). Even in phase III, a significant number of patients seem to have insidious vascular inflammation, which has been demonstrated in surgical specimens and postmortem series.

In advanced cases, occlusion of the vessels to the extremities may result in ischemic ulcerations or gangrene, and with the involvement of cerebral arteries, strokes can occur. Because of the chronic nature of the disease, however, collateral circulation usually develops in the areas involved by vasculitis.

Pathologic changes involved in Takayasu arteritis are the same as for giant cell arteritis. Involved vessel walls develop irregular thickening and intimal wrinkling. Early in the disease, mononuclear infiltration with perivascular cuffing is seen. That extends to the media, followed by granulomatous changes and patches of necrosis and scarring (fibrosis) of all layers, especially the intima. Late stages have lymphocytic infiltration.

The distinction between Takayasu and giant cell arteritis is primarily the clinical pattern of vessels involved. Giant cell arteritis commonly involves the temporal artery, whereas Takayasu arteritis primarily involves the aorta, its main branches, and, in 50% of cases, the pulmonary artery.[1] The initial vascular lesions frequently occur in or at the origin of the left subclavian artery, which can cause weakened radial pulse and easy fatigability in the left arm. As the disease progresses, the left common carotid, vertebral, brachiocephalic, right-middle or proximal subclavian, right carotid, and vertebral arteries, as well as the aorta, also are affected, as well as retinal vessels. The image below illustrates the frequency of vascular involvement in Takayasu in patients in the United States.

Frequency of vascular involvement (adapted from combined reports by Maksimowicz-McKinnon et al and Kerr).

When the abdominal aorta and its branches, eg, the renal arteries, are involved, central hypertension may develop. Accurate blood pressure measurement may be difficult because of arterial lesions affecting supply to the extremities.

Varying degrees of narrowing and occlusion or dilation of involved portions of the arteries result in a wide variety of symptoms.

PreviousNextEpidemiologyFrequencyUnited States

In the United States and Europe, incidence is 1-3 new cases per year per million population. In a cohort of 1204 surgical aortic specimens described by Rojo-Leyva et al[2] , 168 (14%) had inflammation and 52 (4.3%) were classified as having idiopathic aortitis. Among 383 individuals with thoracic aortic aneurysms, 12% had idiopathic aortitis.

International

Vasculitis has a worldwide distribution, with the greatest prevalence among Asians. An extensive epidemiological study conducted in Japan in 1984 identified 20 cases per million population. In 1990, Takayasu arteritis was added to the list of intractable diseases maintained by the Japanese Ministry of Health and Welfare; by the year 2000, 5000 patients were registered (the reported prevalence increased 2.5-fold).

Mortality/Morbidity

The 2 major predictors of poor outcome are complications (eg, Takayasu retinopathy, hypertension, aortic regurgitation, aneurysm) and progressive course.

Patients with no complications or with mild to moderately severe complications have a 10-year survival rate of 100% and a 15-year survival rate of 93-96%. With notable complications or progression, the 10-year survival rate is 80-90% and the 15-year survival rate is 66-68 %.

The occurrence of both a major complication and progressive course predicts the worst outcome (43% survival rate at 15 y).

Sex

Vasculitis is most common among women of reproductive age (female cases outnumber male at a ratio of 9:1).

Age

Aortitis is most commonly discovered at age 10-40 years.

PreviousProceed to Clinical Presentation , Aortitis

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Vertebral Artery Dissection

Practice Essentials

Vertebral artery dissection (VAD) is a relatively rare but increasingly recognized cause of stroke in patients younger than 45 years. Although the term spontaneous VAD is used to describe cases that do not involve significant blunt or penetrating trauma as a precipitating factor, many patients with so-called spontaneous VAD have a history of trivial or minor injury involving some degree of cervical distortion.

Essential update: Long-term benefit from endovascular therapy for vertebral artery dissection

In a study of 73 patients treated for VAD with endovascular internal trapping, stable and durable results were demonstrated over a mean follow-up of 55.6 months. Recanalization was rare and observed only in 2 patients with ruptured VAD, both within 3 months after initial treatment without rupture. Cranial nerve paresis was observed in 8.21% of patients, perforating ischemia was seen in 9.59%, and spinal cord infarction was seen in 2.74%. Patient ratings of quality of life were good.[6]

Signs and symptoms

The typical patient with VAD is a young person who experiences severe occipital headache and posterior nuchal pain following a head or neck injury and subsequently develops focal neurologic signs attributable to ischemia of the brainstem or cerebellum. The focal signs may not appear until after a latent period lasting as long as 3 days, however, and delays of weeks and years also have been reported. Many patients present only at the onset of neurologic symptoms.

When neurologic dysfunction does occur, patients most commonly report symptoms attributable to lateral medullary dysfunction (ie, Wallenberg syndrome). Patient history may include the following:

Ipsilateral facial dysesthesia (pain and numbness)[7] - Most common symptom Dysarthria or hoarseness (cranial nerves [CN] IX and X)Contralateral loss of pain and temperature sensation in the trunk and limbsIpsilateral loss of taste (nucleus and tractus solitarius)HiccupsVertigo[7] Nausea and vomitingDiplopia or oscillopsia (image movement experienced with head motion)Dysphagia (CN IX and X)DisequilibriumUnilateral hearing loss[8]

Rarely, patients may manifest the following symptoms of a medial medullary syndrome:

Contralateral weakness or paralysis (pyramidal tract)Contralateral numbness (medial lemniscus)

Depending upon which areas of the brainstem or cerebellum are experiencing ischemia, the following signs may be present:

Limb or truncal ataxiaNystagmus[9] Ipsilateral Horner syndrome[4] Ipsilateral hypogeusia or ageusia (ie, diminished or absent sense of taste)Ipsilateral impairment of fine touch and proprioceptionContralateral impairment of pain and thermal sensation in the extremities (ie, spinothalamic tract)Lateral medullary syndrome[10]

Cerebellar findings may include the following:

NystagmusMedial medullary syndromeTongue deviation to the side of the lesion (impairment of CN XII)Contralateral hemiparesisIpsilateral impairment of fine touch and proprioception (nucleus gracilis)Internuclear ophthalmoplegia (lesion of the medial longitudinal fasciculus)

See Clinical Presentation for more detail.

Diagnosis

Imaging studies in patients with suspected VAD may include the following:

Computed tomography – Identifies subarachnoid hemorrhage[9] Four-vessel cerebral angiography[11] – Once the criterion standard for diagnosis, now largely supplanted by noninvasive techniques Magnetic resonance imaging[5, 12, 11, 13, 14] – Detects both the intramural thrombus and intimal flap that are characteristic of VAD[11] ; hyperintensity of the vessel wall seen on T1-weighted axial images is considered by some to be pathognomonic of VAD Magnetic resonance angiography[5, 12, 15, 13, 14] – Can identify a pseudolumen and aneurysmal dilation of the artery[11] Vascular duplex scanning – Demonstrates abnormal flow in 95% of patients with VAD,[5] but shows signs specific to VAD (eg, segmental dilation of the vessel, eccentric channel) in only 20% Transcranial Doppler – Approximately 75% sensitive to the flow abnormalities seen in VAD; useful also in detecting high-intensity signals (HITS), which are characteristic of microemboli propagating distally as a result of the dissection

Because VAD occurs in young, generally healthy individuals, laboratory evaluation is directed toward establishing baseline parameters in anticipation of anticoagulant therapy, as follows:

Prothrombin time (PT) with international normalized ratio (INR)Activated partial thromboplastin time (aPTT)

In addition, elevation of the erythrocyte sedimentation rate (ESR) may suggest vasculitis involving the cerebrovascular circulation.

See Workup for more detail.

Management

Acute management of proven or suspected spontaneous VAD is as follows[16] :

Anticoagulants and antiplatelet agents are the drugs of choice to prevent thromboembolic disordersMore potent agents (eg, intra-arterial thrombolytics) have been used in selected cases

See Treatment and Medication for more detail.

Image libraryA, Dissection of the left vertebral artery secondary to guidewire injury. B, Complete resolution occurred in 6 months with only aspirin and clopidogrel (Plavix; Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Bridgewater, NJ) therapy. NextBackground

Vertebral artery dissection (VAD) is an increasingly recognized cause of stroke in patients younger than 45 years.[1, 2, 3, 4] Although its pathophysiology and treatment closely resemble that of its sister condition, carotid artery dissection (CAD), the clinical presentation, etiology, and epidemiological profile of VADs are unique. In particular, advances in imaging have contributed to growing awareness of this entity.[5]

PreviousNextPathophysiology

An expanding hematoma in the vessel wall is the root lesion in VAD. This intramural hematoma can arise spontaneously or as a secondary result of minor trauma, through hemorrhage of the vasa vasorum within the media of the vessel. It also can be introduced through an intimal flap that develops at the level of the inner lumen of the vessel. Major trauma is also an increasingly recognized cause of VAD.[17]

This intramural hemorrhage can evolve in a variety of ways, resulting in any of the following consequences:

The hematoma may seal off and, if sufficiently small, remain largely asymptomatic.If the dissection is subintimal, the expanding hematoma may partially or completely occlude the vertebral artery or one of its branches. Extensive dissections (those that extend intracranially and involve the basilar artery) result in infarctions of the brainstem, cerebellum or, rarely, the spinal cord. Subintimal dissections also may rupture back into the vertebral artery, thus creating a false lumen (pseudolumen). Subadventitial dissections tend to cause pseudoaneurysmal dilation of the vertebral artery, which may compress adjacent neurologic structures. These subadventitial dissections are prone to rupture through the adventitia, resulting in subarachnoid hemorrhage. In an autopsy series of more than 100 patients with subarachnoid hemorrhage, 5% of the hemorrhages were deemed the result of VAD. The intimal disruption and low flow states that arise in VAD create a thrombogenic milieu in which emboli may form and propagate distally. This results in transient ischemia or infarction.

An understanding of the anatomy of the vertebral artery is helpful. The course of the vertebral artery usually is divided into 4 sections as follows:

Segment I runs from its takeoff at the first branch of the subclavian artery to the transverse foramina of cervical vertebra C5 or C6. Segment II runs entirely within the transverse foramina of C5/C6 to C2.Segment III, a tortuous segment, begins at the transverse foramen of C2, runs posterolaterally to loop around the posterior arch of C1, and passes subsequently between the atlas and the occiput. This segment is encased in muscles, nerves, and the atlanto-occipital membrane. Segment IV, the intracranial segment, begins as it pierces the dura at the foramen magnum and continues until the junction of the pons and medulla, where the vertebral arteries merge to join the larger proximal basilar trunk.

Spontaneous dissection of the vertebral artery usually occurs in the tortuous distal extracranial segment (segment III) but may extend into the intracranial portion or segment IV.

PreviousNextEpidemiologyFrequencyUnited States

Dissections of the extracranial cervical arteries are relatively rare. The combined incidence of both VAD and CAD is estimated to be 2.6 per 100,000. However, cervical dissections are the underlying etiology in as many as 20% of the ischemic strokes presenting in younger patients aged 30-45 years. Among all extracranial cervical artery dissections, CAD is 3-5 times more common than VAD.[7]

Mortality/MorbidityVertebral artery dissection (VAD) has been associated with a 10% mortality rate in the acute phase. Death is the result of extensive intracranial dissection, brainstem infarction, or subarachnoid hemorrhage.[10] Those who survive the initial crisis do remarkably well, with long-term sequelae rare.Sex

The female-to-male ratio is 3:1.

Age

In contrast to atherothrombotic disease of the vertebrobasilar circulation, VAD occurs in a much younger population. The average age is 40 years; the average age of a patient with CAD is closer to 47 years.[12]

PreviousProceed to Clinical Presentation , Vertebral Artery Dissection

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Anticoagulants and Thrombolytics in Pregnancy

OverviewOutline of antithrombotic agents

Although the formation of a thrombus or clot within a blood vessel is important for maintaining hemostasis, pathological thrombosis can occur and cause deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, or myocardial infarction (MI). The images below show an overview of the process for diagnosing DVT and PE, respectively.

Diagnosis of deep vein thrombosis during pregnancy. Diagnosis of pulmonary embolism during pregnancy.

Antithrombotic agents (ie, anticoagulants and thrombolytic agents) are first-line therapy for pathological thromboses. Anticoagulants interrupt the coagulation cascade to prevent thrombus formation and extension while endogenous thrombus lysis occurs. They are available in oral or parenteral forms. Thrombolytic agents promote thrombus lysis and are administered parenterally.

Warfarin is an oral anticoagulant that interferes with liver synthesis of vitamin K-dependent clotting factors, which leads to depletion of factors II (prothrombin), VII, IX, and X and prolongation of clotting times (ie, international normalized ratio [INR]). Rivaroxaban is an orally active factor Xa inhibitor that prolongs prothrombin time (PT) and activated partial thromboplastin time (aPTT). Dabigatran is an orally administered direct thrombin inhibitor that results in prolongation of the aPTT. Unlike warfarin, the pharmacokinetics of rivaroxaban and dabigatran are predictable; thus, routine monitoring of coagulation parameters is not required when one of these agents is used. Although warfarin has been used extensively in pregnancy, the safety and efficacy of the newer oral agents (rivaroxaban or dabigatran) in pregnancy has not been established.

The most commonly used parenteral anticoagulants inactivate thrombin and/or factor Xa without depleting circulating levels of clotting factors. Unfractionated heparin, low molecular weight heparin (LMWH), heparinoids, synthetic pentasaccharide inhibitors (eg, fondaparinux), and direct thrombin inhibitors (ie, hirudin and argatroban) belong to this category.

Thrombolytic agents mediate the dissolution of fibrin clots by promoting the conversion of plasminogen to plasmin, which causes degradation of fibrin to fibrin degradation products. Traditional thrombolytic agents include streptokinase (SK), anisoylated plasminogen streptokinase activator complex (APSAC), urokinase, and recombinant tissue plasminogen activator (t-PA).

Evidenced indications for the use of antithrombotic agents

Indications of antithrombotic use have been recently published and include the following:[1]

Acute and chronic venous thromboembolism (including pulmonary embolism )Atrial fibrillationValvular and structural heart diseaseIschemic strokeAcute coronary syndromesPeripheral artery occlusive disease

Pregnancy is associated with 4 times increased risk of venous thromboembolism (VTE) and the risk increases to 14-fold during puerperium.[2] This risk further increases if an underlying thrombophilia is present. PE remains a leading cause of maternal mortality in the Western world.[3] The risk in pregnant women is 5 times higher than in nonpregnant women of the same age.[4]

Anticoagulant therapy is indicated in pregnancy for the treatment acute VTE, valvular heart disease, and for the prevention of pregnancy-related complications in women with antithrombin deficiency or antiphospholipid antibody syndrome (APLAs) and other thrombophilias who have had prior VTE.[5, 6]

NextPathophysiology

Normal pregnancy is associated with a hypercoagulable state due, at least in part, to increased serum levels of procoagulants, such as factor II,[7] VII,[7, 8] VIII,[7] X,[7, 9, 10] XII,[9, 10] and fibrinogen.[7, 11] In addition, protein S levels decrease during pregnancy,[12] and increased resistance to activated protein C is observed in the second and third trimesters of pregnancy.

Concomitantly, serum plasminogen activator inhibitor-1 (PAI-1) and placental plasminogen activator inhibitor-2 (PAI-2) increase with pregnancy which leads to a decreased fibrinolytic state.{Ref12}[13] Venous stasis resulting from pressure of the gravid uterus on the inferior vena cava and decreased venous tone are additional predisposing factors to VTE.

PreviousNextEpidemiology of Venous Thromboembolism in Pregnancy

The incidence of pregnancy-associated VTE is estimated at 1 in 500 to 2000 deliveries (0.05-0.2%).[14, 15] The risk is 4-fold to 50-fold higher in pregnant women than in nonpregnant women and is highest during puerperium.[16, 17] The incidence of VTE in puerperium and pregnancy is 7.19 and 0.97 per 1000 women, respectively.[18] The risk of pregnancy-related VTE is particularly high in heterozygous carriers of factor V Leiden (4-fold to 16-fold increase),[19] the prothrombin mutation (15-fold increase),[20] and women with antiphospholipid antibodies (5% incidence).{{Ref 6}

Most (approximately 85%) of DVT of the lower extremity occur on the left side during pregnancy. This is attributed to the more tortuous course of the venous drainage of the left leg through the pelvis and compression of the left common iliac vein by the overlying right iliac artery.[21]

PreviousNextPrevention and Treatment of Venous Thromboembolism

The following recommendations are part of the Eighth American College of Chest Physicians (ACCP) Conference on Antithrombotics and Thrombolytics Therapy: Evidence Based Guidelines.[22]

Table 1. ACCP Risk Factors and Recommendations (Open Table in a new window)

Risk FactorRecommendationsWomen with a single episode of VTE associated with a transient risk factor that is no longer presentClinical surveillance and anticoagulant prophylaxis postpartum*Women with a single episode of VTE and thrombophilia (confirmed laboratory abnormality) and a strong family history of thrombosis who are not receiving long-term anticoagulants Prophylactic or intermediate-dose LMWH or unfractionated heparin (UFH), plus postpartum anticoagulation for at least 6 wk (for a total minimum duration of therapy of 6 mo) Women with antithrombin deficiency and no previous VTEAntepartum and postpartum prophylaxisWomen with thrombophilia (other than antithrombin deficiency) and no previous VTEClinical surveillance or prophylactic LMWH or UFH and anticoagulant prophylaxis postpartum*Women with multiple (≥ 2) episodes of VTE who are not receiving long-term anticoagulantsProphylactic, intermediate-dose or adjusted-dose UFH or adjusted-dose LMWH followed by long-term anticoagulation postpartumWomen with multiple (≥ 2) episodes of VTE who are receiving long-term anticoagulantsAdjusted-dose UFH or LMWH followed by resumption of long-term anticoagulation postpartumAll women with previous DVT, antenatal and postpartumUse of graduated elastic compression stockingsWomen with recurrent pregnancy loss (≥ 3 miscarriages) and women with severe or recurrent preeclampsia, placental abruption, or otherwise unexplained intrauterine growth retardation Screen for thrombophilia and antiphospholipid antibodiesWomen with antiphospholipid antibody syndrome and a history of multiple (≥ 2) early pregnancy losses or ≥ 1 late pregnancy losses, preeclampsia, intrauterine growth retardation (IUGR), or abruptionAntepartum aspirin plus prophylactic or intermediate-dose UFH or LMWHWomen with APLAs and a history of VTE who are usually receiving long-term oral anticoagulation therapyAdjusted-dose LMWH or UFH therapy plus low-dose aspirin and resumption of long-term oral anticoagulation therapy postpartum* If the previous risk factor is pregnancy or estrogen-related or additional risk factors (such as obesity) are present, antenatal anticoagulant prophylaxis is recommended.

The following are ACCP recommendations for antithrombotic agents.[22] In pregnant women with acute VTE, the following 2 alternative approaches are reasonable:

Subcutaneous LMWH can be used initially and for long-term treatment with dose adjustment based on monitoring of anti-Xa levels.Intravenous (IV) UFH bolus is followed by continuous infusion to maintain aPTT in the therapeutic range for at least 5 days, followed by subcutaneous LMWH or dose-adjusted subcutaneous UFH for the remainder of pregnancy.

LMWH is preferred over UFH for the prevention and treatment of VTE because of ease of use and better efficacy and safety profile. Anticoagulants should be administered for at least 6 weeks postpartum (for a minimum total duration of therapy of 6 mo).

In women receiving dose-adjusted LMWH or UFH therapy, discontinuing anticoagulant therapy 24 hours prior to elective induction of labor is recommended. If spontaneous labor occurs, careful monitoring of aPTT or anti-Xa levels is required. If aPTT is markedly prolonged near delivery, protamine sulfate may be required to reduce the risk of bleeding.

PreviousNextAnticoagulation During Pregnancy in Patients With Valvular Heart Disease

Women with valvular heart disease who are pregnant or planning to conceive require careful evaluation and management. Physiologic changes associated with pregnancy are poorly tolerated in some cases of valvular heart disease. These include aortic stenosis, mitral regurgitation, aortic regurgitation with New York Heart Association (NYHA) class 3-4 symptoms, mitral stenosis with NYHA class 2-4 symptoms, valvular heart disease that results in severe pulmonary hypertension, and left ventricular (LV) dysfunction with an ejection fraction (EF) less than 40%. Patients with mechanical prosthetic valve requiring anticoagulation are exposed to special risks during pregnancy.[23] Therefore, whenever possible, symptomatic or severe valvular lesions should be addressed before conception.

Treatment

Anticoagulation is recommended in most pregnant patients with a mechanical prosthetic heart valve, whereas those with a bioprosthetic valve do not require anticoagulation. Warfarin (Coumadin) is more efficacious than UFH for thromboembolic prophylaxis of pregnant women with mechanical valves.[24] Unfortunately, warfarin therapy in the first trimester of pregnancy is associated with a substantial increase in fetal anomalies, and anticoagulation with any agent is associated with an increased incidence of fetal wastage (approximately 30%), prematurity (approximately 45%), and low birth weight (approximately 50%).[25, 26, 22]

In a systematic review of fetal and maternal outcome of pregnancy with mechanical heart valves, the regimen associated with the lowest risk of valve thrombosis (3.9%) was warfarin throughout pregnancy. However, its use throughout pregnancy was associated with warfarin embryopathy in 6.4% of live births. The substitution of heparin at or prior to 6 weeks, and continued until 12 weeks, eliminated the risk of warfarin embryopathy. Using heparin only from 6-12 weeks' gestation was associated with an increased risk of valve thrombosis (9.2%).

In 2002, the US Food and Drug Administration (FDA) issued a warning that LMWH was not recommended for thromboprophylaxis in pregnant women with prosthetic heart valves. However, a consensus panel concluded that this recommendation was based on studies in which underdosing or inadequate monitoring of LMWH occurred.[27] Consequently, the panel supports the use of LMWH as a treatment option with monitoring of anti-Xa levels. Seshadhri et al reviewed 120 articles and concluded that LMWH, compared with UFH, may be a safe and effective agent in patients with mechanical prosthetic heart valves.[28] However, large-scale, randomized trials are warranted.

PreviousNextRecommendations

Recommendations for anticoagulation of pregnant women with prosthetic heart valves is based on the Eighth ACCP Conference on Antithrombotics and Thrombolytics and are as follows:[22]

Adjusted dose twice daily (bid) subcutaneous LMWH throughout pregnancy to achieve a peak anti-Xa level of 1-1.2 U/mL 4 hours after injection or Adjusted dose bid subcutaneous UFH throughout pregnancy to achieve mid-interval aPTT at least twice control or an anti-Xa level of 0.35-0.70 U/mL or UFH or LMWH (as above) until 13 weeks' gestation, change to warfarin until the middle of the third trimester, and then restart UFH or LMWH

Long-term anticoagulants should be resumed postpartum with all regimens.

High-risk women with prosthetic heart valves, such as women with LV dysfunction and women with prior thromboembolic episodes, should have the addition of low-dose aspirin 75-162 mg/d.

PreviousNextMaternal and Fetal Complications Secondary to AnticoagulationUse of anticoagulants in the breastfeeding mother

Heparin and LMWHs are not secreted into breast milk and can be safely administered to women who are breastfeeding.[29]

Two reports show that maternal administration of warfarin does not induce an anticoagulant effect in the breastfed infant. Thus, women using this drug should be encouraged to breastfeed.[29, 30]

Fetal complications of anticoagulants during pregnancy

Warfarin crosses the placenta and can cause both fetal bleeding and teratogenicity, with the latter occurring mainly during the first trimester.[31]

Neither UFH[32] nor LMWH[33, 34] cross the placenta; therefore, these agents do not cause fetal bleeding or teratogenicity, although bleeding at the uteroplacental junction and fetal wastage is possible.

Maternal complications of anticoagulants during pregnancy

The rate of major bleeding in patients treated with UFH therapy is 2%.[35]

Approximately 3% of patients receiving UFH develop immune thrombocytopenia (so called, heparin-induced thrombocytopenia [HIT]), which predisposes to venous and arterial thrombosis.[36]

Heparin-induced osteoporosis causes vertebral fracture in 2-3% of patients and significant reduction in bone density is seen in about 30% of patients receiving long-term UFH. LMWH causes less osteoporosis and HIT than UFH.[37, 38, 39, 40, 41]

Previous, Anticoagulants and Thrombolytics in Pregnancy

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Aortic Regurgitation

Background

Aortic regurgitation (AR) is the diastolic flow of blood from the aorta into the left ventricle (LV). Regurgitation is due to incompetence of the aortic valve or any disturbance of the valvular apparatus (eg, leaflets, annulus of the aorta) resulting in the diastolic flow of blood into the left ventricular chamber. (See Pathophysiology and Etiology.)

Valvular abnormalities that may result in AR can be caused by the following (see Etiology, Presentation, and Workup):

Congenital causes - Bicuspid aortic valve is the most common congenital cause[1]

Rheumatic feverInfective endocarditisCollagen vascular diseasesDegenerative aortic valve disease

Abnormalities of the ascending aorta, in the absence of valve pathology, may also cause AR. Such abnormalities may occur with the following conditions:

Longstanding, uncontrolled hypertensionMarfan syndromeIdiopathic aortic dilationCystic medial necrosisSenile aortic ectasia and dilationSyphilitic aortitisGiant cell arteritisTakayasu arteritisAnkylosing spondylitisWhipple diseaseOther spondyloarthropathies

Aortic regurgitation may be a chronic disease process or it may occur acutely, presenting as heart failure.[2] The most common cause of chronic aortic regurgitation used to be rheumatic heart disease, but presently it is most commonly caused by bacterial endocarditis.[3] In developed countries, it is caused by dilation of the ascending aorta (eg, aortic root disease, aortoannular ectasia). (See Presentation and Workup.)

Three fourths of patients with significant aortic regurgitation survive 5 years after diagnosis; half survive for 10 years. Patients with mild to moderate regurgitation survive 10 years in 80-95% of the cases. Average survival after the onset of congestive heart failure (CHF) is less than 2 years. (See Prognosis, Treatment, and Medication.)

Acute aortic regurgitation is associated with significant morbidity, which can progress from pulmonary edema to refractory heart failure and cardiogenic shock.

Patient education

The current American College of Cardiology/American Heart Association (ACC/AHA) guidelines for valvular heart disease, including for AR, are available to the public online for free.[4] Additionally, educational and support organizations, such as the National Marfan Foundation and the Bicuspid Aortic Foundation, exist for many of the underlying conditions.

NextPathophysiology

Incompetent closure of the aortic valve can result from intrinsic disease of the cusp, diseases of the aorta, or trauma. Diastolic reflux through the aortic valve can lead to left ventricular volume overload. An increase in systolic stroke volume and low diastolic aortic pressure produces an increased pulse pressure. The clinical signs of AR are caused by the forward and backward flow of blood across the aortic valve, leading to increased stroke volume.[5]

The severity of AR is dependent on the diastolic valve area, the diastolic pressure gradient between the aorta and LV, and the duration of diastole.

The pathophysiology of AR depends on whether the AR is acute or chronic. In acute AR, the LV does not have time to dilate in response to the volume load, whereas in chronic AR, the LV may undergo a series of adaptive (and maladaptive) changes.

Acute aortic regurgitation

Acute AR of significant severity leads to increased blood volume in the LV during diastole. The LV does not have sufficient time to dilate in response to the sudden increase in volume. As a result, LV end-diastolic pressure increases rapidly, causing an increase in pulmonary venous pressure and altering coronary flow dynamics. As pressure increases throughout the pulmonary circuit, the patient develops dyspnea and pulmonary edema. In severe cases, heart failure may develop and potentially deteriorate to cardiogenic shock. Decreased myocardial perfusion may lead to myocardial ischemia.

Early surgical intervention should be considered (particularly if AR is due to aortic dissection, in which case surgery should be performed immediately).

Chronic aortic regurgitation

Chronic AR causes gradual left ventricular volume overload that leads to a series of compensatory changes, including LV enlargement and eccentric hypertrophy. LV dilation occurs through the addition of sarcomeres in series (resulting in longer myocardial fibers), as well as through the rearrangement of myocardial fibers. As a result, the LV becomes larger and more compliant, with greater capacity to deliver a large stroke volume that can compensate for the regurgitant volume. The resulting hypertrophy is necessary to accommodate the increased wall tension and stress that result from LV dilation (Laplace law).

During the early phases of chronic AR, the LV ejection fraction (EF) is normal or even increased (due to the increased preload and the Frank-Starling mechanism). Patients may remain asymptomatic during this period. As AR progresses, LV enlargement surpasses preload reserve on the Frank-Starling curve, with the EF falling to normal and then subnormal levels. The LV end-systolic volume rises and is a sensitive indicator of progressive myocardial dysfunction.

Eventually, the LV reaches its maximal diameter and diastolic pressure begins to rise, resulting in symptoms (dyspnea) that may worsen during exercise. Increasing LV end-diastolic pressure may also lower coronary perfusion gradients, causing subendocardial and myocardial ischemia, necrosis, and apoptosis. Grossly, the LV gradually transforms from an elliptical to a spherical configuration.

PreviousNextEtiologyAcute aortic regurgitation

Infective endocarditis may lead to destruction or perforation of the aortic valve leaflet. A bulky vegetation can also interfere with proper coaptation of the valve leaflets or lead to frank prolapse or disruption of a leaflet (flail leaflet).[3, 6, 7]

Another cause of acute AR, chest trauma, may lead to a tear in the ascending aorta and disruption of the aortic valve support apparatus.

In acute ascending aortic dissection (type A), the retrograde proximal dissection undermines the suspensions of the aortic valve leaflets. Varying levels of aortic valve malcoaptation and prolapse occur. Prosthetic valve malfunction can also lead to AR.

Chronic aortic regurgitation

Bicuspid aortic valve is the most common congenital lesion of the human heart. Although it leads more often to progressive aortic stenosis than to AR, it is nonetheless the most common cause of isolated AR requiring aortic valve surgery. In patients with bicuspid aortic valve, an associated aortopathy may be present, resulting in aortic dilation and/or dissection that worsens the AR.[8]

Certain weight loss medications, such as fenfluramine and dexfenfluramine (commonly referred to as Phen-Fen), may induce degenerative valvular changes that result in chronic AR.

Rheumatic fever, a common cause of AR in the first half of the 20th century, has become less common in the United States, although it remains prevalent in some immigrant populations. Fibrotic changes cause thickening and retraction of the aortic valve leaflets, resulting in central valvular regurgitation. Leaflet fusion may occur, leading to concurrent aortic stenosis. Associated rheumatic mitral valve disease is almost always present.

Ankylosing spondylitis often causes an aortitis, which most frequently involves the aortic root, with associated AR.[9] Further extension of the subaortic fibrotic process into the intraventricular septum may result in conduction system disease. Coronary and more distal aortic abnormalities are also seen in this condition.

Behçet disease causes cardiac complications in less than 5% of patients, but potential findings include proximal aortitis with AR, as well as coronary artery disease.[10]

Giant cell arteritis is a systemic vasculitis that typically affects the extracranial branches of the carotid artery but that may also cause aortic inflammation and AR (as well as coronary artery disease and LV dysfunction).[11]

Rheumatoid arthritis uncommonly causes granulomatous nodules to form within the aortic valve leaflets. In rare cases, this may lead to clinical AR, although it is more commonly an incidental finding postmortem.[12]

Systemic lupus erythematosus can cause valvular fibrosis and consequent dysfunction, including AR.[13] Lupus is also associated with Libman-Sacks endocarditis, resulting in sterile, verrucous valvular vegetations that can cause AR.[14, 15]

Takayasu arteritis, in addition to having aortic valvular (and coronary) involvement, can produce an aortitis. The aortitis may increase the risk of prosthetic valve detachment, leading some to advocate for concurrent aortic root replacement in patients undergoing valve surgery.[16]

Whipple disease has been reported in the literature in association with AR or aortic valve endocarditis.[17]

Connective tissue disorders that can cause significant AR include the following:

Marfan syndromeEhlers-Danlos syndromeFloppy aortic valveAortic valve prolapseSinus of Valsalva aneurysmAortic annular fistulaPreviousNextEpidemiologyOccurrence in the United States

Although rheumatic heart disease is overall the most common cause of AR worldwide, congenital and degenerative valve abnormalities are the most common cause in the United States, with the age of detection peaking at 40-60 years. Estimates of the prevalence of AR of any severity range from 2-30%, but only 5-10% of patients with AR have severe disease, resulting in an overall prevalence of severe AR of less than 1% in the general population.[18]

In the Framingham study (with an original cohort of 5209 patients aged 28-62 y and an additional cohort of 5124 patients), AR of any severity was found in 13% of men and 8.5% of women.[19] Prevalence and severity increased with age; when stratified by decades of life, AR of moderate or greater severity was seen in less than 1% of patients in all strata younger than 70 years.

International occurrence

The prevalence of AR internationally is not well known. However, the international prevalence of underlying conditions has been described elsewhere. For example, rheumatic heart disease remains highly prevalent in many Asian, Middle Eastern, and North African countries.[20]

Race-, sex-, and age-related demographics

The prevalence of AR appears to be similar across racial populations in the United States, although internationally there is significant variation in the prevalence of predisposing conditions, such as rheumatic heart disease.[20]

AR is seen more commonly in men than in women. In the cohort from the Framingham study, AR was found in 13% of men and 8.5% of women.[19] The greater prevalence of AR in men may reflect, in part, the preponderance of underlying conditions, such as Marfan syndrome[21] or bicuspid aortic valve, in males.[22]

Chronic aortic regurgitation often begins in patients when they are in their late 50s and is documented most frequently in patients older than 80 years. In general, the prevalence and severity of AR increase with age, although severe chronic AR is uncommon before age 70 years.[19] However, there are many exceptions to this observation. Patients with bicuspid aortic valve and, especially, those with Marfan syndrome tend to present much earlier.[21, 22]

PreviousNextPrognosis

The prognosis for patients with severe AR depends on the presence or absence of LV dysfunction and symptoms.[4] In asymptomatic patients with normal EF, the following has been found:

Rate of progression to symptoms or LV dysfunction - Less than 6% per yearRate of progression to asymptomatic LV dysfunction - Less than 3.5% per yearRate of sudden death - Less than 0.2% per year

In asymptomatic patients with decreased EF, the rate of progression to symptoms is greater than 25% per year, while in symptomatic patients, the mortality rate is over 10% per year.

The strongest predictors of outcome are echocardiographic parameters (EF and LV end-systolic dimension), underscoring the crucial role of serial echocardiography in the management of patients with severe AR.

Severe acute AR, if left untreated, is likely to lead to considerable morbidity and mortality from either the underlying cause (typically infective endocarditis or aortic dissection) or from hemodynamic decompensation of the LV.

Potential complications in patients with severe chronic AR include progressive LV dysfunction and dilation, congestive heart failure, myocardial ischemia, arrhythmia, and sudden death. Additional complications may arise as a result of the patient's underlying condition (such as aortic root dissection in a patient with a bicuspid aortic valve and a severely dilated aortic root).

Morbidity and mortality

Severe acute AR carries a very high short-term rate of morbidity and mortality owing to the imposition of a greatly increased regurgitant volume upon a relatively noncompliant LV. Increased LV end-diastolic pressure leads to elevated left atrial and pulmonary pressures with resulting pulmonary edema, as well as decreased coronary perfusion gradients that potentially can cause myocardial ischemia and even sudden cardiac death. In most cases, early (if not emergent) surgical intervention is warranted.

Severe chronic AR tends to follow a more gradual clinical course. This is typically characterized initially by a long, relatively asymptomatic period. However, once symptoms ensue, the patient's clinical status may deteriorate relatively rapidly. Thus, current guidelines recommend surgical intervention before symptoms develop, usually based on echocardiographic parameters.

With conservative (medical) management of severe chronic AR, the linearized yearly rates of major events have been estimated as follows[23] :

Death from any cause - 4.7%Congestive heart failure - 6.2%Aortic valve surgery - 14.6%

The presence of symptoms has been found to predict yearly mortality risk, as follows:

Asymptomatic - 2.8%New York Heart Association (NYHA) class I - 3.0%NYHA class II - 6.3%NYHA class III-IV - 24.6%

Although these types of data suggest that a symptom-triggered approach to surgical intervention may be feasible, multiple studies have shown that, as stated earlier, the most important predictors of mortality (and of postoperative LV function) are not symptoms but 2 crucial echocardiographic parameters; specifically, LV ejection fraction and LV end-systolic dimension.[4]

Risk of coronary artery disease

A study by Atalar et al found that in patients with rheumatic valve disease, the prevalence of AR was inversely proportional to the prevalence of significant coronary artery disease. The investigators, who conducted a retrospective analysis of more than 1000 patients with rheumatic valve disease, also found that, while the presence of coronary artery disease was particularly low in patients with AR, it was unusually high in those with aortic stenosis.[24]

PreviousProceed to Clinical Presentation , Aortic Regurgitation

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Libman-Sacks Endocarditis

Background

Libman-Sacks endocarditis (otherwise known as verrucous, marantic, or nonbacterial thrombotic endocarditis) is the most characteristic cardiac manifestation of the autoimmune disease systemic lupus erythematosus. Libman and Sacks first published a description of the atypical, sterile, verrucous vegetations of this form of endocarditis in 1924.[1] The condition most commonly involves the mitral and aortic valves, but all 4 cardiac valves and the endocardial surfaces can be involved.[2]

Postmortem studies describe mulberrylike clusters of verrucae on the ventricular surface of the posterior mitral leaflet, often with adherence of the mitral leaflet and chordae to the mural endocardium. The lesions typically consist of accumulations of immune complexes and mononuclear cells. The condition is not always recognized on echocardiographic images. With the introduction of steroid therapy for systemic lupus erythematosus, improved longevity of patients appears to have changed the spectrum of valvular disease.

Valvular abnormalities occur as masses (classic Libman-Sacks vegetations; see the image below), diffuse leaflet thickening, valvular regurgitation, and, infrequently, stenosis. Valvular regurgitation is noted most commonly in patients with leaflet thickening, which is thought to represent the chronic healed phase of disease. The left-sided valves are involved most often.

Transesophageal image of a mitral valve with masses characteristic of Libman-Sacks endocarditis.

Lesions similar to those described by Libman and Sacks also occur in association with primary or secondary antiphospholipid syndrome. However, the role of antiphospholipid antibodies in the pathogenesis of Libman-Sacks endocarditis is disputed. Malignancy and hypercoagulable states are also associated with the formation of verrucous endocarditis.

Lesions are usually clinically silent, without significant valvular dysfunction. When such dysfunction does occur, however, it can result in cardiac failure. Embolic phenomena and secondary infective endocarditis, although uncommon, can also complicate valvular abnormalities and can cause neurologic and systemic complications. The risk of systemic emboli is increased substantially in the presence of mitral stenosis, atrial fibrillation, or both.

Valvular regurgitation and, rarely, stenosis may result in heart failure and arrhythmias, such as atrial fibrillation.

NextEtiologyAntiphospholipid antibodies

The pathogenesis of Libman-Sacks endocarditis is unknown. However, antiphospholipid antibodies are frequently associated with valvular abnormalities. These autoimmune antibodies are directed against negatively charged phospholipids present in endothelial cell membranes.

Although immunohistologic studies suggest a pathogenetic role for antiphospholipid antibodies, a similar prevalence and severity of valvular disease have been described in lupus patients without these antibodies; their presence does not seem to be required.

Impairment of antithrombotic mechanisms

Impaired antithrombotic mechanisms present in patients with antiphospholipid syndrome, malignancy, and hypercoagulable states may play a role in the pathogenesis of thrombosis and valvular lesions. Areas of endothelial damage caused by turbulence and the jet effect on the left side of the heart are potential sites of platelet and fibrin deposition.

Steroid therapy

Steroid therapy is implicated in the modification of the nature of valvular abnormalities and in the dysfunction observed in patients with systemic lupus erythematosus.

With the introduction of steroid therapy, valvular thickening and regurgitation appear to occur more commonly, with histologically active lesions identified less frequently. However, data are circumstantial and may reflect improved longevity of patients. Firm conclusions cannot be made.

PreviousNextEpidemiology

Valvular abnormalities are commonly detected in patients with lupus. The characteristic Libman-Sacks vegetations are reported postmortem in approximately 50% of fatal lupus cases. Current echocardiographic studies reveal valvular abnormalities in 28-74% of patients, with valvular masses in 4-43% of patients with systemic lupus erythematosus. Higher rates are generally detected with transesophageal imaging and in subjects with antiphospholipid antibodies (41% with masses), although this observation is not universal.

One cohort study reported that Libman-Sacks endocarditis was found in 11% of patients with lupus.[3] Pure mitral regurgitation was the most common valvular abnormality, followed by aortic regurgitation, combined mitral stenosis and regurgitation, and combined aortic stenosis and regurgitation. At baseline, Libman-Sacks endocarditis was significantly associated with underlying lupus disease activity. During the follow-up echocardiograph, patients with previous valvular lesions had worsened valve function, and more patients developed new valvular lesions.

Coexistent leaflet thickening is noted in 71% of patients with valvular masses. Echocardiography detects valvular thickening in 19-52% of patients with systemic lupus erythematosus.

In older patients, who have a longer mean duration of systemic lupus erythematosus and have received a larger cumulative dose of steroids, valves that appear to be thickened and rigid occur more commonly than verrucous vegetations.

The prevalence of regurgitation in patients with thickened valve leaflets has been reported to be as high as 73%.

The prevalence of valvular abnormalities detected during echocardiography in patients with primary antiphospholipid syndrome has been reported at 30-32%. Abnormal echocardiographic findings are most common in individuals with peripheral arterial thromboses, having been noted in up to 64% of patients. Leaflet thickening is the most frequent abnormality, having been noted in 10-24% of patients. Vegetationlike masses occur in 6-10% of patients.

Sex- and race-related demographics

Systemic lupus erythematosus and primary antiphospholipid syndrome occur 5-9 times more often in women; therefore, patients with cardiac valvular lesions are generally young women. In the United States, statistics show systemic lupus erythematosus to be more prevalent in black and Hispanic women.

PreviousNextPrognosis

Longitudinal data of valvular abnormalities are limited. Two series reported no progression of mild or moderate regurgitation to severe regurgitation over a 2- to 3-year period and reported only isolated cases of mildly progressive stenosis.

Prognosis is probably dependent on the underlying disease activity of systemic lupus erythematosus and associated renal and myocardial dysfunction.

Morbidity and mortality

Mortality is undefined. Patients with systemic lupus erythematosus have an increased mortality rate compared with the general population. Cardiovascular mortality is ranked third in these patients but includes a wide spectrum of pathology.

The combined rate of heart failure, valve replacement, thromboembolism, and secondary infective endocarditis has been reported to be as high as 22% in lupus patients with valvular disease, compared with 8% of patients without valvular disease. Most patients do not have clinically significant valvular dysfunction.

Regurgitation is noted on echocardiographic images in 25-61% of patients with lupus and in 10-24% of patients with primary antiphospholipid syndrome. The prevalence of moderate or severe regurgitation has been reported in 0-12% (severe in 3%, moderate in 9%) of patients with antiphospholipid syndrome and in 4-26% of patients with lupus. The reported need for valve replacement varies from 1-8% of cases.

The occurrence of clinically significant embolic phenomena is thought to be low. Although stroke rates are higher in patients with lupus and antiphospholipid syndrome, multifactorial etiologies for neurologic events are often present, making the specific contribution of valvular abnormalities difficult to determine.

The likely prevalence of secondary infective endocarditis is low, but it has not been widely reported. Potential contributing factors to infective endocarditis are systemic lupus erythematosus, medications prescribed for lupus, and underlying valvular abnormalities.

PreviousNextPatient Education

Give patients on anticoagulation written information regarding potential drug interactions, dietary advice, the need for regular monitoring of the international normalized ratio, and the warning symptoms of hemorrhage. Referral to an anticoagulation clinic may be appropriate.

Educate patients about the need for antibiotic prophylaxis in case of lacerations or in instances of dental work or other procedures.

Information regarding systemic lupus erythematosus is available through the following Web sites:

Arthritis FoundationLupus Foundation of AmericaNational Institutes of Health

For patient education information, see Lupus (Systemic Lupus Erythematosus).

PreviousProceed to Clinical Presentation , Libman-Sacks Endocarditis

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Thoracic Aneurysm

Background

Thoracic aortic aneurysm (TAA) is a life-threatening condition that causes significant short- and long-term mortality due to rupture and dissection. Aneurysm is defined as dilatation of the aorta of greater than 150% of its normal diameter for a given segment. For the thoracic aorta, a diameter greater than 3.5 cm is generally considered dilated, whereas greater than 4.5 cm would be considered aneurysmal.

Aneurysms may affect one or more segments of the thoracic aorta, including the ascending aorta, the arch, and the descending thoracic aorta. As many as 25% of patients with TAA also have an abdominal aortic aneurysm. Thoracic aortic aneurysm most commonly results from degeneration of the media of the aortic wall as well as from local hemodynamic forces.

Descending thoracic aortic aneurysm with mural thrombus at the level of the left atrium. NextPathophysiology

Degenerative changes in the wall of the aorta lead to cystic medial necrosis. This causes damage to collagen and elastin, loss of smooth muscle cells, and increased amounts of basophilic ground substance in the medial (elastic) layer of the aorta. The ascending thoracic aorta is generally most affected by cystic medial necrosis, whereas a descending thoracic aneurysm is primarily a consequence of atherosclerosis.

In Marfan syndrome, abnormalities of the gene encoding for the synthesis of fibrillin have been implicated in the predisposition to form aneurysms. Mutations in the gene responsible for this structural lipoprotein found in the aortic wall have been found in patients who do not have Marfan syndrome but have aneurysms.

As many as 75% of patients with a bicuspid aortic valve have shown evidence for cystic medial necrosis, which may be because of inadequate fibrillin production. Other inherited forms of medial degeneration have been associated with defects in the genes for fibrillin and are associated with higher rates of thoracic aortic aneurysm (TAA).

Weakening of the aortic wall is compounded by increased shear stress, especially in the ascending aorta. This segment of the aorta is most exposed to the pressure of each cardiac systole (dP/dt) as well as the dynamic heart motion transmitted from each cardiac cycle. As local wall weakness causes dilatation of the aorta, wall tension increases (described by the Laplace law (T=PR), where wall tension equals the radius of a cylinder multiplied by the pressure within it). Small tears in the intimal (innermost) layer of the aorta can permit blood to penetrate the medial layer, leading to aortic dissection.

PreviousNextEpidemiologyFrequencyUnited States

The incidence of aortic aneurysm is 5.9 cases per 100,000 person-years.[1]

Mortality/Morbidity

The cumulative risk of rupturing a thoracic aortic aneurysm (TAA) is related to aneurysm diameter. In a recent series of 133 patients with TAA, risk of rupture at 5 years was 0% for diameter less than 4 cm, 16% for diameter 4-5.9 cm, and 31% for aneurysms greater than 6 cm in diameter.[2]

Race

Thoracic aortic aneurysm is most common among whites.

Sex

Men are affected 2-4 times more frequently than women.

Age

The mean patient age at diagnosis is 60-65 years.

PreviousProceed to Clinical Presentation , Thoracic Aneurysm

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Mitral Valve Prolapse

Practice Essentials

Mitral valve prolapse (MVP) is the most common valvular abnormality, affecting approximately 2-6% of the population in the United States. MVP usually has a benign course, but it occasionally leads to serious complications, including clinically significant mitral regurgitation, infective endocarditis, sudden cardiac death, and cerebrovascular ischemic events.

Essential update: More accurate imaging of mitral valve prolapse with 3D echocardiography

Real-time 3-dimensional transesophageal echocardiography (3D TEE) is superior to 2-dimensional TEE for quantifying MVP in patients with severe mitral regurgitation, according to a study of 102 patients with severe mitral regurgitation due to MVP, mitral valve flail, or both. Compared with 3D TEE, 2D TEE underestimated the width of the prolapse and the leaflet gap. In addition, because of the complicated anatomy of the mitral valve, 2D imaging could not detect the largest prolapse gap and width.[1]

Signs and Symptoms

Most patients with MVP are asymptomatic. Symptoms are related to one of the following:

Autonomic dysfunctionProgression of mitral regurgitationAn associated complication (ie, stroke, endocarditis, or arrhythmia)

Symptoms related to autonomic dysfunction are usually associated with genetically inherited MVP and include the following:

AnxietyPanic attacksArrhythmiasExercise intolerancePalpitationsAtypical chest painFatigueOrthostasisSyncope or presyncopeNeuropsychiatric symptoms

Symptoms related to progression of mitral regurgitation include the following:

FatigueDyspneaExercise intoleranceOrthopneaParoxysmal nocturnal dyspnea (PND)Progressive signs of chronic heart failure (CHF)

Common general physical features associated with MVP include the following:

Asthenic body habitusLow body weight or BMIStraight-back syndromeScoliosis or kyphosisPectus excavatumHypermobility of the jointsArm span greater than height (which may be indicative of Marfan syndrome)

The classic auscultatory finding is a mid-to-late systolic click. It may or may not be followed by a high-pitched, mid-to-late systolic murmur at the cardiac apex. These can vary with the following maneuvers:

A Valsalva maneuver or having the patient stand result in an early click, which is close to the first heart sound, and a prolonged murmur The supine position, especially with the legs raised, results in a click later in systole and a shortened murmur

See Clinical Presentation for more detail.

Diagnosis

Findings on echocardiography are as follows:

Classic MVP: The parasternal long-axis view shows > 2 mm superior displacement of the mitral leaflets into the left atrium during systole, with a leaflet thickness of at least 5 mm Nonclassic MVP: Displacement is > 2 mm, with a maximal leaflet thickness of

Other echocardiographic findings that should be considered as criteria are leaflet thickening, redundancy, annular dilatation, and chordal elongation

See Workup for more detail.

Management

For purposes of treatment, patients with MVP can be divided into the following categories:

Asymptomatic patients with minimal diseasePatients with symptoms of autonomic dysfunctionPatients with evidence of progression to severe mitral regurgitationPatients with neurologic findingsPatients with a mid-systolic click and late-systolic mitral regurgitation murmur

Treatment measures for asymptomatic patients with minimal disease

Strong reassurance of the benign prognosisInitial echocardiography for risk stratification; if no clinically significant mitral regurgitation and thin leaflets are observed, clinical examinations and echocardiographic studies can be scheduled every 3-5 years Encouragement to pursue a normal, unrestricted lifestyle, including vigorous exercise

Treatment measures for patients with symptoms of autonomic dysfunction

A trial of beta-blockers for symptomatic reliefAbstinence from stimulants such as caffeine, alcohol, and cigarettesAn ambulatory 24-hour monitor may be useful to detect supraventricular and/or ventricular arrhythmias

Treatment measures for patients with evidence of or progression to severe mitral regurgitation

Close follow-up and early referral for surgical repair, before left ventricular dilatation and systolic dysfunction developSurgery before left ventricular function deteriorates in asymptomatic patients with moderate-to-severe mitral regurgitation and left ventricular enlargement, especially those with atrial fibrillation and/or pulmonary hypertension Treadmill stress test for exercise tolerance if the physician is unsure the patient is asymptomatic

Treatment measures for patients with neurologic findings

After atrial fibrillation and left atrial thrombus are excluded, daily aspirin therapy at a dosage of 80-325 mg/dCessation of smoking and oral contraceptive use to prevent a hypercoagulable stateWarfarin therapy for patients older than 65 years who have atrial fibrillation, especially if they have associated risk factors of a previous stroke or TIA, clinically significant valvular heart disease, hypertension, diabetes, left atrial enlargement, or a history and/or findings of heart failure

Treatment measures for patients with a mid-systolic click and late-systolic mitral regurgitation murmur

Consider antibiotic prophylaxis, including for patients with increased leaflet thickening or redundancyAntibiotic prophylaxis is not recommended for the patient with an isolated mid-to-late systolic click without a murmur, unless the echocardiogram demonstrates significant leaflet redundancy and/or thickness

See Treatment and Medication for more detail.

NextBackground

Mitral valve prolapse (MVP) is the most common valvular abnormality, affecting approximately 2-6% of the population in the United States. MVP usually results in a benign course. However, it occasionally leads to serious complications, including clinically significant mitral regurgitation, infective endocarditis, sudden cardiac death, and cerebrovascular ischemic events. MVP is also the most common cause of isolated mitral regurgitation in the United States, and it is the most common reason for mitral valve surgery.

PreviousNextPathophysiology

Most patients with MVP are asymptomatic, and their natural history is benign. However, when large, floppy valves or ruptured chordae tendinea result in severe mitral regurgitation, mitral valve surgery or repair may be necessary. Myxomatous proliferation is the most common pathologic basis for MVP, and it can lead to myxomatous degeneration of the loose spongiosa and fragmentation of the collagen fibrils. Disruption of the endothelium may predispose patients to infectious endocarditis and thromboembolic complications. However, the vast majority of patients with MVP have only a minor derangement of the mitral valve structure that is usually clinically insignificant.

PreviousNextFrequencyUnited States

MVP is thought to be inherited with increased expression of the gene in female individuals (2:1). The most common form of inheritance is autosomal dominant, but X-linked inheritance has been described.

MVP commonly occurs with heritable connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum. In fact, 90% of patients with Marfan syndrome have MVP due to the increased redundancy of the mitral leaflets and apparatus that occur as a result of myxomatous degeneration.

In the 1970s and 1980s, MVP was overdiagnosed because of the absence of rigorous echocardiographic criteria, with a reported prevalence of 5-15%. Subsequently, Levine et al reported that the 2-dimensional echocardiographic characterizations of prolapse, especially on the parasternal long-axis view, are most specific for the diagnosis of MVP. Use of these criteria prevent overdiagnosis.

Data from the community-based Framingham study demonstrated that MVP syndrome occurred in only 2.4% of the population.

PreviousNextMortality/Morbidity

Most patients with MVP are asymptomatic and have a benign prognosis, with survival rates similar to those of the general population. Nonetheless, high-risk patients (ie, those with moderate-to-severe mitral regurgitation) have increased cardiac morbidity and mortality rates, especially if reduced left ventricular systolic function is present.

See Complications.

Sex

MVP occurs more frequently in young women than in men. The most serious consequences of hemodynamically significant mitral regurgitation occur in men older than 50 years.

Age

MVP has been observed in all ages.

PreviousProceed to Clinical Presentation  Contributor Information and DisclosuresAuthor

Bhavik V Thakkar, MD  Medical Director, Internal Medicine Hospitalist, AppleCare Medical Group
Bhavik V Thakkar, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Heart Association, American Medical Association, American Stroke Association, Minnesota Medical Association, and Society for Vascular Medicine and Biology
Disclosure: Nothing to disclose.

Coauthor(s)

Adam E Schussheim, MD  Consulting Staff, Department of Internal Medicine, Bridgeport Hospital of the Yale-New Haven Medical Center
Disclosure: Nothing to disclose.

Specialty Editor Board

Justin D Pearlman, MD, ME, PhD, FACC, MA  Chief, Division of Cardiology, Director of Cardiology Consultative Service, Director of Cardiology Clinic Service, Director of Cardiology Non-Invasive Laboratory, Director of Cardiology Quality Program KMC, Dartmouth-Hitchcock Medical Center, Dartmouth Medical School
Justin D Pearlman, MD, ME, PhD, FACC, MA is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Federation for Medical Research, International Society for Magnetic Resonance in Medicine, and Radiological Society of North America
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

Marschall S Runge, MD, PhD  Charles and Anne Sanders Distinguished Professor of Medicine, Chairman, Department of Medicine, Vice Dean for Clinical Affairs, University of North Carolina at Chapel Hill School of Medicine
Marschall S Runge, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American College of Cardiology, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Federation for Medical Research, American Heart Association, American Physiological Society, American Society for Clinical Investigation, American Society for Investigative Pathology, Association of American Physicians, Association of Professors of Cardiology, Association of Professors of Medicine, Southern Society for Clinical Investigation, and Texas Medical Association
Disclosure: Pfizer Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; Orthoclinica Diagnostica Consulting fee Consulting

Amer Suleman, MD  Private Practice
Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal Society of Medicine, and Society of Cardiac Angiography and Interventions
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

Alan D Forker, MD Professor of Medicine, University of Missouri at Kansas City School of Medicine; Director, Outpatient Lipid Diabetes Research, MidAmerica Heart Institute of St Luke's Hospital

Disclosure: Nothing to disclose.

References

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Kligfield P, Hochreiter C, Kramer H, et al. Complex arrhythmias in mitral regurgitation with and without mitral valve prolapse: contrast to arrhythmias in mitral valve prolapse without mitral regurgitation. Am J Cardiol. Jun 1 1985;55(13 Pt 1):1545-9. [Medline].

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Levine RA, Stathogiannis E, Newell JB, et al. Reconsideration of echocardiographic standards for mitral valve prolapse: lack of association between leaflet displacement isolated to the apical four chamber view and independent echocardiographic evidence of abnormality. J Am Coll Cardiol. May 1988;11(5):1010-9. [Medline].

Levine RA, Stathogiannis E, Newell JB, et al. Reconsideration of echocardiographic standards for mitral valve prolapse: lack of association between leaflet displacement isolated to the apical four chamber view and independent echocardiographic evidence of abnormality. J Am Coll Cardiol. May 1988;11(5):1010-9. [Medline].

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Ling LH, Enriquez-Sarano M, Seward JB, Orszulak TA, Schaff HV, Bailey KR. Early surgery in patients with mitral regurgitation due to flail leaflets: a long-term outcome study. Circulation. Sep 16 1997;96(6):1819-25. [Medline].

MacMahon SW, Hickey AJ, Wilcken DE, Wittes JT, Feneley MP, Hickie JB. Risk of infective endocarditis in mitral valve prolapse with and without precordial systolic murmurs. Am J Cardiol. Jan 1 1987;59(1):105-8. [Medline].

MacMahon SW, Roberts JK, Kramer-Fox R, et al. Mitral valve prolapse and infective endocarditis. Am Heart J. May 1987;113(5):1291-8. [Medline].

Markiewicz W, Stoner J, London E, Hunt SA, Popp RL. Mitral valve prolapse in one hundred presumably healthy young females. Circulation. Mar 1976;53(3):464-73. [Medline].

Marks AR, Choong CY, Sanfilippo AJ, et al. Identification of high-risk and low-risk subgroups of patients with mitral-valve prolapse. N Engl J Med. Apr 20 1989;320(16):1031-6. [Medline].

Martínez-Rubio A, Schwammenthal Y, Schwammenthal E, Block M, Reinhardt L, Garcia-Alberola A. Patients with valvular heart disease presenting with sustained ventricular tachyarrhythmias or syncope: results of programmed ventricular stimulation and long-term follow-up. Circulation. Jul 15 1997;96(2):500-8. [Medline].

Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. Nov 1 2001;345(18):1318-30. [Medline].

Nidorf SM, Weyman AE, Hennessey R. The relationship between mitral valve morphology and prognosis in patients with mitral valve prolapse: a prospective echocardiographic study of 568 patients [abstr]. J Am Soc Echocardiogr. 1993;6:S8.

Nishimura RA, McGoon MD. Perspectives on mitral-valve prolapse. N Engl J Med. Jul 1 1999;341(1):48-50. [Medline].

Nishimura RA, McGoon MD, Shub C, Miller FA Jr, Ilstrup DM, Tajik AJ. Echocardiographically documented mitral-valve prolapse. Long-term follow-up of 237 patients. N Engl J Med. Nov 21 1985;313(21):1305-9. [Medline].

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Pulmonic Regurgitation

Background

The pulmonic valve is normally a thin tricuspid structure that prevents blood from regurgitating into the right ventricle once ejected into the low-pressure pulmonary circulation. Pulmonic regurgitation refers to retrograde flow from the pulmonary artery into the right ventricle during diastole. Physiologic (trace-to-mild) pulmonic regurgitation is present in nearly all individuals, particularly in those with advanced age. However, pathologic conditions that produce excessive and clinically significant regurgitation can result in impairment of right ventricular function and eventual clinical manifestations of right-sided volume overload and heart failure. Often, pulmonic regurgitation is not the primary process but a finding secondary to an underlying process such as pulmonary hypertension or dilated cardiomyopathy.

NextPathophysiology

Incompetence of the pulmonic valve occurs by 1 of 3 basic pathologic processes: dilatation of the pulmonic valve ring, acquired alteration of pulmonic valve leaflet morphology, or congenital absence or malformation of the valve.

PreviousNextEpidemiologyFrequencyUnited States

Physiologic pulmonic regurgitation is present in nearly all individuals and is a normal echocardiographic finding. Pulmonic regurgitation detected by physical examination is not a normal finding in healthy adults. Congenital pulmonic regurgitation and congenital absence of the pulmonic valve are rare conditions.

International

No difference in international incidence is known.

Mortality/Morbidity

The morbidity and mortality rates associated with pulmonic regurgitation vary considerably, depending on the underlying etiology.

Race

No racial or ethnic predilection exists.

Sex

Differing frequency of pulmonic regurgitation between men and women corresponds to the specific etiology resulting in pulmonic regurgitation.

Age

Except for congenital absence of the pulmonic valve, which is more likely to cause right-sided ventricular decompensation early in life, the age at which clinical symptoms of pulmonic regurgitation occur is variable and is primarily related to the underlying process causing the pulmonic regurgitation.

PreviousProceed to Clinical Presentation , Pulmonic Regurgitation

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Rheumatic Fever

Background

Acute rheumatic fever (ARF) is an autoimmune inflammatory process that develops as a sequela of streptococcal infection. ARF has extremely variable manifestations (see the image below) and remains a clinical syndrome for which no specific diagnostic test exists. Persons who have experienced an episode of ARF are predisposed to recurrence following subsequent (rheumatogenic) group A streptococcal infections. The most significant complication of ARF is rheumatic heart disease, which usually occurs after repeated bouts of acute illness.

Clinical manifestations and time course. NextPathophysiology

ARF is characterized by nonsuppurative inflammatory lesions of the joints, heart, subcutaneous tissue, and central nervous system. An extensive literature search has shown that, at least in developed countries, rheumatic fever follows pharyngeal infection with rheumatogenic group A streptococci.[1, 2, 3, 4] The risk of developing rheumatic fever after an episode of streptococcal pharyngitis has been estimated at 0.3-3%.[1] More recent investigations of rheumatic fever occurring in the aboriginal populations of Australia suggest that streptococcal skin infections might also be associated with the development of rheumatic fever.[5, 6] In Oceania and Hawaii, streptococcal strains that are not typically associated with rheumatic fever have been found to cause the disease.[7]

Molecular mimicry accounts for the tissue injury that occurs in rheumatic fever. Both the humoral and cellular host defenses of a genetically vulnerable host are involved. In this process, the patient's immune responses (both B- and T-cell mediated) are unable to distinguish between the invading microbe and certain host tissues.[8] The resultant inflammation may persist well beyond the acute infection and produces the protean manifestations of rheumatic fever.

PreviousNextEpidemiologyFrequencyUnited States

The incidence of ARF has declined markedly in the past 50 years in both the United States and Western Europe. Most Western physicians see only the late sequelae of rheumatic heart disease; the diagnosis of an acute case is usually reason enough for a ground rounds presentation. This remarkable decline of rheumatic fever likely reflects improved socioeconomic conditions, as well the decline in prevalence of the classically described rheumatogenic strains of group A streptococci.

Following two decades of almost total absence, a resurgence of ARF occurred in the 1980s among middle-class white children in Salt Lake City, Utah.[9] Clusters were also reported in US Army and Navy training camps during the same period.[10] These limited outbreaks were associated with mucoid rheumatogenic strains that were rarely seen in the preceding 20 years. Today, ARF remains a rarity in most of the United States, although Hawaii and American Samoa continue to see a significant number of cases, many of which are caused by streptococcal strains not usually associated with rheumatic fever in persons of Polynesian descent.[7, 11]

International

In developing countries, the magnitude of ARF is enormous. Recent estimates suggest that 15.6 million people worldwide have rheumatic heart disease and that 470,000 new cases of rheumatic fever (approximately 60% of whom will develop rheumatic heart disease) occur annually, with 230,000 deaths resulting from its complications. Almost all of this toll occurs in the developing world.[12, 13] The incidence rate of rheumatic fever is as high as 50 cases per 100,000 children in many areas. Areas of hyperendemicity (eg, indigenous populations of Australia and New Zealand) see an incidence of 300-500 cases per 100,000 children, while the rates are approximately 50-fold lower in their nonindigenous compatriots.[6] Rheumatic fever in the 21st century appears to be largely a disease of crowding and poverty.

Mortality/Morbidity

Cardiac involvement is the most serious complication of rheumatic fever and causes significant morbidity and mortality. As stated above, about 60% of the approximately 470,000 patients diagnosed with ARF annually eventually develop carditis, joining the approximately 15 million worldwide with rheumatic heart disease. Those with rheumatic heart disease are at a high risk for additional cardiac damage with subsequent bouts of ARF and require secondary prophylaxis. Morbidity due to congestive heart failure (CHF), strokes, and endocarditis is common among individuals with rheumatic heart disease, and about 1.5% of persons with rheumatic carditis die of the disease annually.[12, 6]

Race

ARF is predominantly a disease of developing countries and is concentrated in areas of deprivation and crowding. It is rampant in the Middle East, in sub-Saharan Africa, in the Indian subcontinent, in certain areas of South America, in Polynesia, and among the indigenous populations of Australia and New Zealand. Although a genetic predisposition to ARF clearly exists,[1] the disease does not seem to have a major racial predisposition, as it was once common in the United States and Europe and seems to decline in any locale where living conditions improve.

Sex

Rheumatic fever does not have a clear-cut sexual predilection, although certain clinical manifestations, such as mitral stenosis and Sydenham chorea, are more common in females who have gone through puberty.

Age

ARF is most common among children aged 5-15 years. It is relatively rare in infants and uncommon in preschool-aged children. ARF occurs in young adults, but the incidence of first episodes of ARF falls steadily after adolescence and is rare after age 35 years.[6] The lower rate of ARF in adults may represent a decreased risk of streptococcal pharyngitis in this cohort. Recurrent episodes, with their predisposition to cause or exacerbate valvular damage, occur until middle age.

PreviousProceed to Clinical Presentation , Rheumatic Fever

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