Manual of Cardiovascular Medicine

I.Introduction. Several systemic diseases involve the cardiovascular system, with important therapeutic and prognostic implications. It is vital for cardiologists to recognize, manage, and prevent cardiovascular involvement in various systemic diseases. This chapter reviews the cardiovascular manifestations of various systemic disorders.

II.Rheumatologic Disorders

A.Rheumatoid arthritis (RA) is one of the commonest forms of chronic inflammatory polyarthritis resulting in joint destruction and deformation. It affects 1% to 3% of the population and is more common in women. The most common cardiovascular manifestations of RA are as follows:

1.Pericarditis can present in nearly 50% of patients with RA. It can vary from acute pericarditis and chronic asymptomatic effusive pericarditis to cardiac tamponade or chronic constrictive pericarditis, with significant hemodynamic consequences. Most cases with uncomplicated acute pericarditis will respond to nonsteroidal anti-inflammatory drugs (NSAIDs). Corticosteroid therapy may be needed for patients with severe pericarditis.

2.Coronary artery disease (CAD). Cardiovascular disease is the leading cause of death in patients with RA because of accelerated atherosclerosis, likely a result of chronic systemic inflammation and use of corticosteroids. After controlling for traditional risk factors of atherosclerosis, patients with RA have been shown to have two to three times greater risk of CAD compared with controls. In the large prospective Nurses’ Health Study, women with RA were found to have a twofold higher risk of myocardial infarction compared with controls. In a more recent study, ischemic heart disease was found in 16.6% of RA patients compared with 12.8% of controls. In addition to disease-modifying drugs to reduce systemic inflammation, aggressive lifestyle modification, including tight control of blood pressure and low-density lipoprotein cholesterol, is warranted.

3.Cardiomyopathy. RA can cause granulomatous inflammation of the myocardium leading to cardiomyopathy or involve the conduction system resulting in varying degrees of heart block. Rarely, secondary amyloidosis can occur in RA, leading to an infiltrative cardiomyopathy.

4.Valvular disease. A small proportion of patients with RA can have valvular involvement in the form of rheumatoid nodules; however, clinically significant valve disease is very rare.

B.Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that occurs more commonly in women and is characterized by a wide range of organ involvement, including arthritis, dermatitis, glomerulonephritis, serositis, and hematologic abnormalities. Drug-induced lupus can occur with various cardiac medications, including procainamide, quinidine, and hydralazine, and this is associated with the development of antihistone antibodies. SLE can affect the cardiovascular system in various ways:

1.Valvular disease is the most common type of cardiac involvement in SLE. The characteristic valvular lesions in SLE are nonmobile, noninfectious vegetations on the atrial aspect of the mitral valve or the arterial aspect of the aortic valve, referred to as Libman–Sacks endocarditis (Fig. 36.1). Studies have shown that valvular involvement is very common in SLE and occurs in >50% of patients. The most common valvular abnormality is valvular thickening, followed by vegetations and valvular regurgitation or stenosis. Serial echocardiography should be performed to monitor for progression of valve disease. The vegetations can embolize and cause stroke or myocardial infarction in rare cases (Fig. 36.1).

FIGURE 36.1 Transesophageal echocardiogram demonstrating vegetations (Libman–Sacks endocarditis) on the atrial aspect of anterior and posterior mitral valve leaflets in a patient with systemic lupus erythematosus. A: Zoom view of the valve leaflets. B: A less detailed image of the leaflets. LA, left atrium; LV, left ventricle.

2.Pericarditis is very common in SLE and has been shown to occur in >50% to 60% of patients. Associated pericardial effusion is usually exudative, with elevated protein and low glucose concentration, and infection must be ruled out in the setting of concomitant immunosuppressive therapy. Cardiac tamponade and chronic constrictive pericarditis can also occur. NSAIDs can be tried first in mild cases of pericarditis. Colchicine can be tried alongside NSAIDs. Systemic steroids can be considered in patients that are not responsive to NSAIDs and colchicine.

3.Coronary artery disease. Premature coronary atherosclerosis has been shown to occur commonly in patients with SLE compared with age-matched controls. CAD can also manifest as coronary arteritis, thrombosis in the presence of antiphospholipid antibody (APLA) syndrome (see Section II.C), or, rarely, embolism from Libman–Sacks endocarditis.

4.Myocardial dysfunction in patients with SLE can result from ischemia, valve disease, or long-standing hypertension. Patients with peripheral skeletal myositis have an increased risk of lupus myocarditis.

5.Conduction system disease with complete heart block can occur in infants born to mothers with SLE, particularly those with anti-Ro and anti-La antibodies. Women with SLE contemplating pregnancy should undergo screening for these antibodies prior to pregnancy and, if present, should undergo fetal echocardiography to screen for conduction abnormalities and myocardial dysfunction. There is some evidence suggesting a role for intrauterine dexamethasone in reversing fetal myocarditis and slowing conduction disease.

C.Antiphospholipid antibody syndrome is characterized by the presence of antiphospholipid antibodies or lupus anticoagulant, recurrent venous or arterial thrombosis, and miscarriages. APLAs can occur independently, referred to as primary APLAs, or can be associated with other autoimmune diseases such as SLE (10% to 30%) and are then referred to as secondary APLAs. Valvular disease is common in APLAs and is characterized by noninfectious vegetations similar to those seen in SLE (Libman–Sacks endocarditis). Management of arterial or venous thrombosis or significant valvular vegetations includes anticoagulation therapy with warfarin. Monitoring anticoagulant effect while on heparin or warfarin may be difficult, because these patients can have prolonged partial thromboplastin time or international normalized ratio at baseline, in which case monitoring of anticoagulant effect can be done using activity levels of factors II and X.

D.Scleroderma or systemic sclerosis is a rare autoimmune disorder, characterized by vasospasm, microvascular occlusion, and fibrosis of skin and multiple organs. Cardiovascular involvement can occur in progressive as well as limited scleroderma.

1.Pericardial disease in the form of fibrinous pericarditis is present in over 70% of patients on autopsy studies, although it is clinically manifest as symptomatic pericarditis in only about 15% to 30% of patients. Small pericardial effusions can be detected in about 40% of patients by echocardiography, but are rarely significant. Acute pericarditis may be treated with NSAIDs, with close monitoring of renal function. Corticosteroids carry the risk of inducing scleroderma renal crisis.

2.Pulmonary hypertension (PH) is responsible for significant morbidity and mortality in patients with scleroderma and is more common in the limited type. Autopsy studies have shown histopathologic changes consistent with PH in 65% to 80% of patients with scleroderma; however, <10% of patients manifest PH clinically. Patients with scleroderma and PH appear to have a worse prognosis compared with those with primary PH, with a 2-year survival of <50%. Drugs for PH, such as prostacyclins (epoprostenol, treprostinil, and iloprost), endothelin receptor antagonists (bosentan and ambrisentan), and phosphodiesterase inhibitors (sildenafil and tadalafil), have been studied in patients with scleroderma and PH. Combination therapies including the use of warfarin may improve survival in patients with PH from systemic sclerosis. Echocardiography should be used to screen for asymptomatic PH.

3.Myocardial involvement with patchy fibrosis can occur in patients with scleroderma. Epicardial coronary arteries are usually normal on angiography; however, ischemia can occur secondary to microvascular vasospasm. Diastolic dysfunction has been commonly found in these patients. Electrical abnormalities such as frequent ectopy, supraventricular arrhythmias, and nonsustained ventricular tachycardia (VT) can occur in patients with progressive systemic sclerosis. The risk of sudden cardiac death is higher in those with a history of syncope.

E.Seronegative spondyloarthropathies include HLA-B27 antigen–associated arthropathies such as ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and inflammatory bowel disease–associated arthritis. These disorders occur more commonly in males. Proximal aortitis with or without aortic regurgitation and conduction disturbances are most commonly associated with ankylosing spondylitis and reactive arthritis. Proximal aortitis can lead to thickening, stiffness, and dilatation of the aortic root with aortic regurgitation. Aortic or mitral valve thickening with nodularities of the aortic cusps and thickening of the anterior mitral valve leaflet resulting in a characteristic subaortic bump are commonly observed valvular abnormalities in patients with ankylosing spondylitis. Extension of the subaortic inflammation and fibrotic process into the basal septum can result in conduction abnormalities such as heart block, which is usually at the level of the atrioventricular (AV) node. Other less common cardiac abnormalities include pericarditis, diastolic dysfunction, and supraventricular arrhythmias.

F.Dermatomyositis (DM) and polymyositis (PM) are idiopathic inflammatory myopathies characterized by proximal skeletal muscle weakness and elevated levels of muscle enzymes, such as creatine kinase and aldolase. Cardiovascular manifestations of DM and PM include pericarditis, conduction abnormalities, and congestive heart failure secondary to myocarditis that can be focal or generalized and may be steroid responsive. Cardiac magnetic resonance imaging (MRI) with delayed gadolinium enhancement may be useful in monitoring response to therapy. Coronary vasculitis is a rare manifestation. Management of DM and PM includes corticosteroids, and adjunctive therapies include methotrexate, azathioprine, and intravenous immunoglobulin (IVIg).

III.Systemic Vasculitides

A.Giant cell arteritis (GCA), also referred to as temporal arteritis, is the most common vasculitis in patients older than 50 years. It is more prevalent in women compared with men and in those of Northern European descent. GCA usually affects the extracranial branches of the aorta, sparing the intracranial vessels. Transmural inflammation of the vessels is followed by intimal hyperplasia, luminal occlusion, and end-organ ischemia. Branches of the external and internal carotid arteries are particularly susceptible, and the typical clinical presentation of GCA includes new-onset headache, scalp and temporal artery tenderness, jaw pain, acute visual loss, and polymyalgia rheumatica. Concomitant elevation in erythrocyte sedimentation rate (ESR) is almost always present. Temporal artery biopsy is the gold standard for diagnosis and shows transmural chronic granulomatous inflammation with destruction of elastic laminae. Treatment with corticosteroids should be initiated as soon as possible, without waiting for temporal artery biopsy. GCA is associated with thoracic and abdominal aortic aneurysms. According to one study, patients with GCA are 17 times more likely to develop thoracic aortic aneurysm and 2.4 times more likely to develop abdominal aortic aneurysm compared with age-matched controls. Rare cardiovascular manifestations include pericarditis, myocarditis, and coronary vasculitis. Studies have shown that MRI or fluorine-18-deoxyglucose positron emission tomography (FDG PET) can be useful for the detection of large vessel vasculitis. Transthoracic echocardiography and abdominal ultrasonography are useful in screening for thoracic and abdominal aortic aneurysms. Low-dose aspirin should be added to corticosteroids, because it has been shown to reduce the rate of blindness and stroke in patients with GCA.

FIGURE 36.2 Magnetic resonance angiogram in a patient with Takayasu arteritis demonstrating severe diffuse narrowing of both common carotid arteries and severe disease in the left subclavian artery (arrows).

B.Takayasu arteritis (TA) is also a large vessel vasculitis like GCA, but it occurs in young women, particularly of Indian, Japanese, and African-American descent. It typically affects the aorta and its major branches (Fig. 33.2). In TA, arterial stenoses are more common than aneurysms. Clinically, TA is characterized by claudication (upper extremities more common compared with lower extremities), “pulselessness” or asymmetric pulses, and blood pressure. Systemic symptoms such as fever, malaise, arthralgias, myalgias, night sweats, and elevated ESR may indicate active disease. Renal artery stenosis can be associated with hypertension. Cardiac manifestations include aortic regurgitation secondary to aortic root dilatation and rarely coronary arteritis. Diagnosis is based on imaging studies that show vascular involvement typical of TA. Imaging modalities such as MRI and PET enable visualization of inflammation in the vessel wall. Therapeutic strategies include corticosteroids, immunosuppressants such as cyclophosphamide or methotrexate in steroid-resistant cases, and anatomic correction using an endovascular or surgical approach when feasible.

C.Kawasaki disease is an acute febrile illness that affects children, usually below the age of 5 years, with the highest incidence in those of Asian descent. Cardiovascular manifestations include pericarditis, myocarditis, aortitis, aortic regurgitation, and arrhythmias. Coronary vasculitis can occur, which if left untreated can lead to coronary aneurysm formation in about 4 weeks. Aneurysms larger than 8 mm are referred to as giant aneurysms, and these can thrombose acutely, leading to myocardial infarction as well as sudden death. Treatment with aspirin and single-dose IVIg (dose 2 g/kg) reduces the formation and progression of coronary aneurysms. Recommendations by the American Heart Association include long-term follow-up and consideration of anticoagulation for children with multiple giant coronary aneurysms or known obstructive lesions, chronic low-dose aspirin therapy, and coronary artery bypass or percutaneous intervention if lesions are severe and symptomatic.

D.Idiopathic aortitis is commonly associated with disorders such as TA and GCA in addition to rheumatologic diseases such as SLE, Behçet disease, seronegative spondyloarthropathies, antineutrophil cytoplasmic antibody–associated vasculitides, Cogan syndrome, and sarcoidosis. Although most cases of aortitis are noninfectious in etiology, infectious causative agents such as staphylococcus, streptococcus, salmonella, and syphilis must be considered. Aortitis can be diagnosed for the first time in surgically excised specimens after aortic surgery. In a 20-year review of over 1,200 aortic surgical specimens at Cleveland Clinic, 52 (4.3%) were clinically and pathologically classified as idiopathic aortitis. Of these, 67% were women. In 96% of cases with idiopathic aortitis and aneurysm formation, aortitis was limited to the thoracic aorta. In 96% of cases, signs of systemic illness were not present at the time of aortic surgery. In 31% (16 of 52), aortitis was associated with a remote history of vasculitis and a variety of other systemic disorders such as GCA, TA, SLE, and Wegener’s granulomatosis. Over a mean follow-up of 41 months, new aneurysms were found in 6 of 25 patients not treated with corticosteroids. It is prudent to follow these patients with serial imaging to identify new aneurysms. Treatment with corticosteroids requires evidence of an ongoing systemic inflammatory disease.

E.Churg–Strauss syndrome (CSS) is a rare small vessel vasculitis characterized by asthma, peripheral eosinophilia, pulmonary infiltrates, and varying degrees of cutaneous, renal, neurologic, and cardiac involvement. Cardiovascular manifestations are common in CSS and are responsible for significant morbidity and mortality in these patients. The most common cause of death is congestive heart failure secondary to cardiomyopathy, the cause of which may be small vessel vasculitis or eosinophilic infiltration of the myocardium followed by fibrosis or a combination of both pathologic processes. Other cardiac manifestations include myocarditis and pericarditis with or without pericardial effusion. Therapy mainly includes corticosteroids but other immunosuppressants may be needed.

F.Polyarteritis nodosa is a rare nongranulomatous disease affecting medium-sized arteries that leads to weakening of the vessel wall secondary to necrotizing changes with aneurysm formation or intimal proliferation and stenosis. Cardiac manifestations include angina, myocardial infarction, congestive heart failure, and arrhythmias such as supraventricular tachycardia. Treatment is similar to CSS and primarily includes corticosteroids.

IV.Connective Tissue Diseases

A.Marfan syndrome was first described over 100 years ago by Antoine-Bernard Marfan, a French pediatrician. It is an autosomal dominant connective tissue disease secondary to mutations in the fibrillin-1 gene (FBN1) that encodes major constituent proteins of microfibrils, which form a significant component of the extracellular matrix. It is a common heritable condition with an estimated prevalence of 1 per 3,000 to 5,000 individuals. About 25% cases have no family history and are a result of de novo mutations. However, genetic evaluation of first-degree relatives is recommended in all instances. The diagnosis of Marfan syndrome is based on the Ghent criteria, based on the consensus by an international expert panel, which have been revised recently with more weight on cardiovascular manifestations. In the absence of family history, the presence of aortic root aneurysm or aortic dissection and ectopia lentis establishes the diagnosis of Marfan syndrome. In the absence of either of these two, the presence of FBN1 gene mutation or a combination of systemic manifestations listed above is required. Cardiovascular manifestations of the Marfan syndrome are as follows:

1.Aortic aneurysm and dissection. Defect in microfibrils results in degeneration of elastic fibers in the aortic media (sometimes inappropriately referred to as “cystic medial necrosis”), with the resultant aortic aneurysm formation. This typically occurs at the level of the aortic root and involves the sinuses of Valsalva. The aortic root diameter should be serially monitored with echocardiography or computed tomography/MRI. According to the current guidelines, annual imaging is recommended if stability in aortic root size is documented. If the baseline aortic diameter is >4.5 cm or if there is significant growth from baseline, more frequent imaging should be considered. Elective surgical repair should be considered if the maximal cross-sectional area in square centimeters of the ascending aorta or root divided by the patient’s height in meters exceeds a ratio of 10, because shorter patients have dissection at a small size and 15% of patients with Marfan syndrome have dissection at an aorta size smaller than 5.0 cm. This threshold is smaller than for other disorders with aortic aneurysm, given the greater tendency for aortic dissection at smaller diameters in patients with Marfan syndrome. Indications for earlier repair at sizes <5.0 cm include rapid growth defined as >0.5 cm/y, family history of aortic dissection at a diameter <5.0 cm, the presence of significant aortic regurgitation, or in female patients contemplating pregnancy with an ascending aortic diameter >4.0 cm. If the aortic root is <4 cm, then the risk of dissection is considered low, and pregnancy can be allowed with β-blocker therapy and careful monitoring with serial echocardiography throughout pregnancy. Aortic regurgitation usually occurs secondary to aortic root dilatation. Aortic dissection in Marfan syndrome is usually type A, that is, starts in the ascending aorta and can extend to a variable degree distally. About 10% of dissections in Marfan syndrome begin distal to the origin of the left subclavian artery (type B). Type A dissection necessitates immediate repair, given the high risk of life-threatening complications if not treated promptly. Medical management in patients with Marfan syndrome includes β-blockers, which have been shown to reduce the risk of aortic dilatation and aortic dissection. The beneficial effect of β-blockers is largely due to the reduction in heart rate and the rate of pressure increase in the aorta, which leads to less stress on the aortic wall. Angiotensin receptor blockade with losartan has been shown to slow the rate of aortic root dilatation in animal models of Marfan syndrome, secondary to mitigation of excessive transforming growth factor β-signaling. However, the evidence for its use in humans is less compelling although a trial of its use in children with Marfan syndrome suggested efficacy similar to β-blockade in reducing aortic dilatation. Certainly, it seems appropriate to consider its use in Marfan patients with adequate blood pressure on β-blockade. Calcium blockers have been associated with higher risk of dissection and should be avoided. Because of the risk of acute aortic dissection, patients with Marfan syndrome should be counseled to avoid isometric exercise, including heavy weight lifting, contact sports, and competitive athletics.

2.Mitral valve prolapse commonly occurs in patients with Marfan syndrome and is more common in women. The incidence is as high as 60% to 80%, and progressive mitral regurgitation occurs in about 25% of patients. The valve leaflets are usually thickened and redundant, and occasionally ruptured chordae or prolapse may be present. Progressive untreated mitral regurgitation can lead to left ventricular dilatation, congestive heart failure, and PH. Tricuspid valve prolapse can occur concomitantly. Standard management for chronic severe mitral regurgitation is indicated in symptomatic patients, with repair of the mitral apparatus if possible, but replacement may be necessary when the leaflets are very redundant or there is severe annular calcification or chordal damage.

3.Dilated cardiomyopathy independent of, or out of proportion to, valvular abnormalities can occur in patients with Marfan syndrome. This has been hypothesized to be secondary to a potential role of fibrillin mutations in the reduction of myocardial function.

4.Arrhythmias, both supraventricular and ventricular, can occur in patients with Marfan syndrome.

B.Loeys–Dietz syndrome (LDS) is an autosomal dominant connective tissue disease with similarities to the Marfan syndrome but with important genotypic and phenotypic differences. It is caused by mutations in the genes encoding transforming growth factor β receptors 1 and 2 (TGFBR1 and TGFB2). Type I LDS is characterized by arterial tortuosity and aneurysms, most often in the aortic root but can involve other arteries, hypertelorism (widely spaced eyes), and bifid uvula or cleft palate or both. Patients are predisposed to more aggressive and widespread vascular disease, including aneurysm formation and dissection, compared with Marfan syndrome, with a mean age of death of 26 years. Patients with LDS can develop aortic dissection at aortic diameters <5 cm; hence, elective repair is recommended at much smaller aortic root dimensions (4.2 cm) compared with Marfan syndrome. Surgical repair has not been associated with tissue fragility in patients with LDS. More than 50% of patients with LDS can develop aneurysms of other vessels; hence, yearly surveillance imaging of the entire vascular tree has been recommended.

C.Ehlers–Danlos syndrome, type IV or vascular form, is a rare autosomal dominant disorder associated with mutations in the gene for type III procollagen (COL3A1). Arterial rupture or dissections are the major causes of mortality in these patients and can occur in the thoracic or abdominal vessels, including aortic rupture or dissection. The median age of survival was about 48 years in a study of 220 patients with this disorder. In the same study, 25% of patients had a medical or surgical complication by the age of 25 years and >80% had such complications by the age of 40 years. In contrast to LDS, tissues are friable in Ehlers–Danlos syndrome, and surgical repair after ruptured aneurysm or dissection can be complicated by hemorrhage or poor wound healing. The role of prophylactic surgical repair for unruptured aneurysms is unclear. Pregnant women have a 50% chance of transmitting the disorder to the child and about 11.5% risk of mortality. Pregnancy should be considered high risk, and women should be counseled against it.

V.Other Systemic Diseases

A.Sarcoidosis is an idiopathic systemic granulomatous inflammatory disease affecting mainly the lungs, but can involve the lymph nodes, skin, eyes, heart, kidneys, musculoskeletal system, nervous system, and endocrine system. Cardiac involvement is found in 25% of patients with sarcoidosis on autopsy, but only 5% of patients have clinically apparent cardiac involvement. The most common sites of cardiac involvement are the basal interventricular septum, AV node and the His bundle, focal regions in the ventricular free walls, and the papillary muscles. Cardiovascular manifestations of sarcoidosis are as follows:

1.Arrhythmias can vary from conduction disturbances, including heart block to fatal ventricular arrhythmias. Complete heart block is the most common abnormality in patients with clinically evident sarcoidosis and is found in 20% to 30% of patients. First-degree heart block and bundle branch blocks are also seen. Granulomatous infiltration of the ventricular myocardium can set up foci of automaticity, leading to ventricular arrhythmias. VT is the most common arrhythmia and is reported in about 20% of patients with sarcoidosis. Sudden cardiac death caused by an arrhythmia is one of the leading causes of death (>60%) in patients with sarcoidosis.

2.Congestive heart failure may occur secondary to widespread infiltration of the myocardium. It may also occur because of arrhythmias, cor pulmonale from long-standing PH, valvular abnormalities, or a combination of these abnormalities. Progressive congestive heart failure is the second most common cause of death in patients with sarcoidosis.

3.Pericardial involvement can manifest as pericarditis, pericardial effusion, and constrictive pericarditis.

Diagnosis of cardiac sarcoidosis may be difficult. Endomyocardial biopsy with finding of noncaseating granulomas has high specificity, but poor sensitivity owing to the patchy nature of myocardial involvement particularly in the basal septum, whereas the location of biopsy is often the apical septum. Electrocardiogram often reveals conduction abnormalities but has poor sensitivity. Echocardiographic findings include increased ventricular septal thickness (secondary to granulomatous expansion) or wall thinning (because of fibrosis), aneurysms, regional wall motion abnormalities, and eventually ventricular dilatation. Contrast-enhanced MRI and 18-FDG PET are more sensitive modalities for detecting early cardiac involvement, and findings correlate with disease severity. These imaging modalities can be used in evaluating response to therapy. Corticosteroid therapy can halt cardiac disease progression and improve survival; however, it does not prevent sudden cardiac death. Pacemaker implantation is often necessary in cases of symptomatic heart block or asymptomatic high-grade conduction disease. Implantable cardioverter defibrillator implantation is recommended for primary prevention in patients with cardiac sarcoidosis at risk for sudden cardiac death, such as those with a history of nonsustained VT or low ejection fraction. Cardiac transplantation for cardiac sarcoidosis is rarely used, because the disease can recur in the transplanted heart. However, it may be considered in young patients with severe end-stage heart failure or resistant VT.

ACKNOWLEDGMENTS: The author thanks Dr. Sachin S. Goel for his contributions to earlier edition of this chapter.

Key References

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Relevant Book Chapters

Villa-Forte A, Mandell BF. Rheumatologic diseases and the cardiovascular system. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: Elsevier Saunders; 2012:1876–1892.