CHAPTER 100: RHEUMATOLOGIC DISEASES AND THE CARDIOVASCULAR SYSTEM

Rheumatologic conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and the vasculitides that affect multiple organ systems may also impact the cardiovascular system. These pathologic processes fall in the category of autoimmune diseases, which are initiated by a complex interplay between genetic factors and environmental stimuli. They are presumed to be driven by self-reactive T and B lymphocytes, which in tandem with a network of endogenous and exogenous signals, activate the immune system, producing tissue inflammation and damage (Table 100–1). The effects of autoimmunity on the cardiovascular system may be the result of local or systemic mechanisms. For example, locally aberrant immunity may selectively target the pericardium, myocardium, or conduction system in systemic sclerosis. On the other hand, in patients with SLE or systemic vasculitis, circulating immune complexes may deposit in blood vessels, where they evoke an inflammatory response, which in turn occludes the vessel lumen and causes ischemic manifestations distal to the site of critically limited blood flow. A hypercoagulable state from antiphospholipid antibody syndrome can lead to thrombotic occlusion, producing myocardial infarction, stroke, or ischemic damage of the visceral organs. Thus, diverse pathways of a dysregulated immune system may converge to directly or indirectly damage the heart and vasculature.

This chapter aims to familiarize the cardiovascular specialist with the clinical features of rheumatologic diseases that affect the heart and blood vessels. These diseases derive from chronic inflammation and abnormal tissue repair. This chapter also covers the most common heritable diseases of connective tissue (eg, Marfan syndrome, Loeys-Dietz, Ehlers-Danlos, and pseudoxanthoma elasticum). Unlike autoimmune diseases, these rare disorders mostly result from mutations in specific genes encoding various components of connective tissue that maintain the structural integrity of the vasculature.

Rheumatoid Arthritis

The prevalence of RA in the Western world is 1% to 2%, and is believed to be 1% worldwide¹; RA thus ranks as the most common of the systemic autoimmune diseases. RA is a female-predominant disease characterized by a chronic symmetrical polyarthritis with a strong predilection for the small joints of the hands and feet that often leads to physical impairment and disability. The diagnosis is established on clinical grounds by recognizing the signs and symptoms of joint inflammation. It is supported by the results of laboratory studies and plain radiographs of the hands and feet. Approximately three-quarters of patients with RA test positive for serum rheumatoid factor or anticyclic citrullinated peptide antibodies.² X-rays of the hands and feet are often normal at the onset of RA, but later they may show the characteristic marginal joint erosions associated with this disease, as well as joint space narrowing from thinning of the articular cartilage. Much is known about the pathogenesis of synovial inflammation in RA. Briefly, the synovial tissue is characterized by a chronic inflammatory infiltrate comprised chiefly of T cells, B cells, macrophages, fibroblasts, and mast cells. There is increased production of a diverse array of proinflammatory mediators, such as tumor necrosis factor (TNF) α, interleukin (IL)-1, and IL-6, as well as many chemokines that work together to amplify the pathologic response, stimulate proliferation of synovial fibroblasts, upregulate expression of adhesion molecules on the surface of blood vessels, and promote angiogenesis.

Although RA is predominately an inflammatory joint disease, it produces systemic effects that can target other organs and tissues. Extraarticular manifestations include fatigue, low-grade fever, Sjögren syndrome, nodules, interstitial lung disease, and vasculitis. In RA, the most common cardiovascular manifestations are pericarditis, valvular disease, cardiomyopathy, coronary vasculitis, ischemic heart disease, and heart failure.

Pericarditis

In a necropsy series, evidence of pericarditis can be seen in as many as 54% of cases of RA.³ Acute, symptomatic pericarditis, however, occurs in fewer than 10% of patients with severe RA.^4,5 RA patients with acute pericarditis are clinically indistinguishable from those with pericardial disease secondary to nonrheumatic conditions. Symptoms of positional chest pain may be reported or a pericardial friction rub may be apparent in up to 55% to 65% of patients.^6,7 Although in this setting electrocardiograms are often normal, 5% to 10% of patients may manifest abnormalities classically associated with acute pericarditis. Imaging may be useful in confirming the diagnosis of pericarditis. In one series, echocardiography revealed a pericardial effusion in 90% of patients with this clinical diagnosis.⁶ Aspiration of the pericardial fluid, which is not usually required for diagnosis in the appropriate clinical setting, may reveal an elevated white blood cell count, protein, and lactate dehydrogenase; decreased glucose level; the presence of rheumatoid factor; and a low complement.⁷ These features may help to differentiate RA pericarditis from other causes of pericarditis.

In one cohort, the occurrence of pericarditis was associated with decreased survival at 10 years.⁶ However, it is unlikely that the presence of pericarditis directly contributes to the increased risk of death as the presence of extraarticular disease in general is associated with increased mortality. Constrictive pericarditis, albeit rare, is associated with higher mortality than is uncomplicated pericarditis. It requires an urgent intervention, such as pericardial window or stripping procedure.⁸ Constrictive pericarditis must be distinguished from restrictive cardiomyopathy, which may result from secondary amyloidosis rarely seen in patients with longstanding RA. Most patients with uncomplicated acute pericarditis will respond to treatment with nonsteroidal anti-inflammatory drugs or corticosteroids. Corticosteroid therapy is generally reserved for patients with moderate-to-severe pericarditis and usually consists of a short burst of high doses of prednisone (eg, 40-60 mg/d) with subsequent taper over a period of several weeks, depending on the clinical response.

Valvular Disease

Clinically significant valvular disease is relatively uncommon in RA. In autopsy reviews, only 3% to 5% of patients with RA had valvular involvement in the form of rheumatoid nodules.^9,10 Patients with subcutaneous rheumatoid nodules have a higher rate of mitral valve insufficiency than those without nodules,¹¹ but unlike patients with rheumatic heart disease, mitral valve disease associated with RA does not lead to valvular stenosis. Patients with severe or symptomatic valvular disease require surgical intervention.^12,13

Cardiomyopathy

RA may cause a cardiomyopathy characterized by focal necrotizing or granulomatous myocarditis.⁴ The granulomas may involve the conduction system, leading to varying degrees of atrioventricular block, which usually persists despite immunosuppressive therapy.¹⁴ Rarely, cardiomyopathy may result from secondary amyloidosis, which manifests on echocardiography as a significant thickening of walls of the ventricles and of the interventricular septum.¹⁵ Cardiac magnetic resonance imaging (MRI) may be used to differentiate the different causes of cardiomyopathy in patients with RA. Inflammation due to granulomatous myocarditis could be seen as multiple focal areas of increased myocardial signal intensity on T2-weighted images.¹⁶ Images from cardiac MRI showing delayed enhancement with gadolinium display a characteristic diffuse endocardial hyperenhancement pattern that may suggest cardiac amyloidosis.¹⁷

Coronary Vasculitis

Although as many as 20% of patients with RA show histologic evidence of coronary vasculitis by autopsy, the significance of this finding is poorly understood because it rarely manifests clinically.⁹ The diagnosis of coronary vasculitis involving the epicardial vessels may be suggested by the angiographic findings of interspersed areas of smooth-walled stenosis and ectasia as well as focal aneurysms. However, these angiographic features are relatively nonspecific and may be due to atherosclerosis. Recognition of coronary vasculitis is important because it requires treatment with immunosuppressive therapy such as high-dose corticosteroids and possibly other agents.¹⁸

Accelerated Coronary Artery Atherosclerosis and Heart Failure

Overall mortality is increased in patients with RA compared with the general population.^19,20 It is striking that 40% of deaths in RA are attributable to cardiovascular disease.^21,22 In a recent study, the prevalence of cardiovascular disease in RA patients was comparable to that of patients with diabetes.²³ It is known that a significant proportion of patients with RA judged to be in clinical remission using standardized disease activity scores still show an elevated level of C-reactive protein (> 3 mg/L), a known risk factor for future cardiovascular death in patients with RA.²⁴ Increasing evidence supports a strong link between RA and accelerated atherosclerosis, highlighting it as an important risk factor for cardiovascular disease.

Atherosclerosis is an inflammatory process driven by many of the same mediators that are associated with rheumatoid inflammation.²⁵ Systemic inflammation in RA is hypothesized to accelerate atherosclerosis, as well as affect other tissues, such as liver, muscle, and fat, which influence other cardiovascular risk factors (Fig. 100–1). Additionally, RA appears to be an independent risk factor for multivessel coronary artery disease,²⁶ and as shown in the Nurses’ Health Study, women with RA have a two-fold higher rate of myocardial infarctions compared with controls.²⁷ Other studies suggest that RA patients are less likely to be symptomatic from ischemic heart disease than non-RA controls, and twice as likely to have sudden death and unrecognized myocardial infarction,²⁸ contributing to a higher incidence of death from coronary atherosclerosis.²⁹

Congestive heart failure also contributes to excess cardiovascular mortality in RA.³⁰ In recent echocardiographic studies, left ventricular (LV) systolic dysfunction was three times more common in RA patients compared with the general population.³¹ Both right ventricular (RV)and LV diastolic dysfunction (measured as a decrease in tricuspid E/A ratio by pulse wave Doppler) has been documented in this disease population despite the lack of clinically evident cardiovascular disease.³² Other findings in RV diastolic dysfunction include lower peak E-wave velocity, and prolonged RV isovolumic relaxation time. Tricuspid E-wave deceleration time was significantly shorter only in those who had an LV restrictive filling pattern. The mechanisms by which RA patients develop heart failure are likely multifactorial depending on the underlying disease process (eg, myocarditis, amyloidosis, ischemia from accelerated atherosclerosis). It is important to note, however, that despite not having risk factors such as obesity or hypertension, patients with heart failure associated with RA still have an increased mortality.³³

There is currently a lack of evidence-based guidelines for the management and prevention of cardiovascular disease in RA patients. In treating RA, the primary goal is tight control of joint inflammation, with conventional disease-modifying anti-rheumatic agents (eg, methotrexate) as well as biologic therapy (eg, TNFα inhibitors, tocilizumab, abatacept). A recent meta-analysis showed that methotrexate was associated with a 21% lower risk for cardiovascular disease and an 18% lower risk for myocardial infarction.³⁴ TNFα inhibitors are generally avoided in RA patients with a history of heart failure because of increased morbidity and mortality in non-RA patients with congestive heart failure who were treated with such therapy.³⁵ In general, traditional cardiovascular risk factors should be aggressively managed in patients with RA until further studies have evaluated the relative benefits and risks of this approach.³⁵

Adult-Onset Still Disease

Adult-onset Still disease refers to a syndrome, usually affecting young adults, that presents with polyarthritis in the setting of fever, evanescent rash, and sore throat (similar to systemic juvenile inflammatory arthritis in children). Pericarditis is the most common cardiac manifestation of adult-onset Still disease, occurring in up to 24% of patients.³⁶ There have been recent case reports, albeit rare, of pericarditis complicated by life-threatening cardiac tamponade.³⁷ Adult-onset Still disease is usually treated with corticosteroids and methotrexate, although TNFα inhibitors, such as etanercept and adalimumab, and the IL-1 antagonists, such as anakinra and rilonacept, as well as tocilizumab (anti-IL-6 receptor antibody), appear to be promising alternatives for severe or refractory cases.

Systemic Lupus Erythematosus

SLE is a much less common systemic autoimmune disease that primarily affects young women, with peak incidence between the ages of 15 and 40 years. In the United States, its prevalence is estimated to be 1 in 2000 individuals and more commonly affects Hispanics and African Americans than Caucasians.³⁸ Although more than 95% of SLE patients test positive for serum antinuclear antibodies, not all patients who are positive for antinuclear antibodies have SLE. Clinically, SLE patients are a heterogeneous group, with a wide range of disease severity and spectrum of organ system involvement. Cardiovascular involvement, in particular, occurs commonly in patients with SLE. It is noted in up to 70% of patients at autopsy^39,40,41 as well as antemortem on echocardiography.^41,42,43,44

The pathogenesis of SLE is likely to be multifactorial with dependence on genetic risk factors. The mechanisms of disease are complex, with contributions from both aberrantly regulated innate (eg, increased expression of genes stimulated by type 1 interferon) and adaptive immune responses (eg, autoantibodies). However, several lines of evidence support a prominent role for immune complex deposition in disease mechanisms, which may be relevant to the pathogenesis of vasculitis and possibly acceleration of atherosclerosis in SLE.

Pericarditis

The most common cardiovascular manifestation of SLE is pericarditis,⁴⁵ with up to 42% of patients in one echocardiographic study showing an effusion.⁴³ Pericardial effusions may be detected at any point in the disease and are usually asymptomatic and small. Acute pericarditis may occur in as many as 20% to 30% of patients with SLE.⁴⁶ Rarely, acute pericarditis may be associated with cardiac tamponade⁴⁷; chronic pericarditis may occasionally lead to constriction.⁴⁸ Particular attention must be paid to differentiating lupus pericarditis from infectious causes in the setting of concomitant immunosuppressive therapy for SLE.⁴⁶ Treatment of lupus pericarditis depends on its severity. Although no therapy is required for asymptomatic, small effusions, symptomatic, acute pericarditis may warrant treatment with nonsteroidal anti-inflammatory drugs or corticosteroids. Moderate or severe acute lupus pericarditis is usually treated with a course of prednisone beginning at 40 to 60 mg daily followed by a subsequent taper in the dose over several weeks according to the clinical response.

Valvular Disease

Valvular disease associated with SLE can be quite common and take on many forms. Libman-Sacks endocarditis is characterized by noninfectious verrucous vegetations seen on cardiac valves (Fig. 100–2). Although any of the four valves may be affected, valvular abnormalities occur most commonly on the mitral valve followed in frequency by the aortic valve.⁴⁵ Valvular lesions are not uncommon, but usually are asymptomatic. According to one series, more than 50% of patients with SLE had valvular abnormalities by transesophageal echocardiography.⁴⁹ The most common abnormality in this study was valvular thickening, followed by vegetations, and then valvular insufficiency. The significance of valve thickening is unknown and may resolve over time or worsen. Complications of valvular vegetations included cerebral and/or coronary artery thromboemboli,^50,51 although the absolute risk is very low. Other abnormalities that have been reported in SLE include valvulitis,⁵² valve fibrosis and mucoid degeneration, and aortic dissection.⁵³

There is a lack of consensus regarding the use of corticosteroids for treatment of valvular vegetations or other abnormalities. Valve replacement surgery is the usual course of action for the management of patients with clinically symptomatic or hemodynamically significant valve disease.^52,54 A less invasive transcatheter approach may be a future consideration in lupus patients deemed too high risk for surgery.⁵⁵ Although patients with lupus may have an increased lifetime risk of acquisition of infective endocarditis due to valvular abnormalities, the most recent American Heart Association guidelines do not recommend routine antibiotic prophylaxis for dental procedures in this patient population.⁵⁶

Myocardial Disease

Myocardial dysfunction in SLE may result from valvular disease, coronary artery ischemia, or sustained hypertension and, in some cases, can lead to clinically significant heart failure. Lupus cardiomyopathy, which is defined as a cardiomyopathy in the absence of ischemic disease or hypertension, has been reported in many series, but is not well understood from a pathophysiologic perspective.⁵⁷ Acute myocarditis should be suspected in any patient with SLE who presents with new-onset arrhythmia, fever, dyspnea, and chest pain. The diagnosis of lupus myocarditis is often based on clinical grounds after evaluation by coronary angiography and other cardiac imaging procedures. Cardiac enzymes are not usually elevated in lupus myocarditis. The role of endomyocardial biopsy is not well established; it is subject to sampling error, and the sensitivity and specificity of the biopsy findings in myocarditis are unknown.⁵⁶ Treatment of clinically significant myocarditis typically calls for high doses of prednisone therapy for a prolonged course of 3 to 6 months with or without other immunosuppressive agents.

Conduction System Disease and Neonatal Lupus

Lupus myocarditis may be complicated by tachyarrhythmias and conduction system disturbances. Additionally, injury to the conduction system, a rare occurrence, may result from small-vessel vasculitis, leading to various forms of atrioventricular block. Pericarditis may be associated with atrial fibrillation and flutter, although these are usually transient. Unexplained sinus tachycardia may also occur in SLE patients without obvious cardiac involvement and usually resolves with steroid therapy.⁴⁶

A conduction system abnormality may occur in infants of mothers with SLE whose serum contains anti-Ro and anti-La antibodies. Some of these mothers may also have been previously diagnosed with primary Sjögren syndrome, whereas others may appear healthy. Fewer than 5% of women with anti-Ro and/or anti-La antibodies will give birth to infants with neonatal lupus syndrome or congenital heart block. Congenital heart block develops from the transmission of maternal anti-Ro and anti-La antibodies to the fetus, causing myocardial inflammation and fibrosis.⁵⁹ Additionally, the probability of congenital heart block increases to almost 20% in subsequent offspring.⁵⁸ High-risk mothers with these serologic features should undergo fetal echocardiograms to look for evidence of myocardial dysfunction or screen for conduction system abnormalities by detecting a prolonged mechanical PR interval to identify a potentially reversible block.⁶⁰ Treatment with dexamethasone may be helpful in converting first- and second-degree heart block; however, third-degree heart block appears largely irreversible.⁶¹

Coronary Artery Disease

Coronary artery disease is prevalent in SLE and has emerged as a significant cause of morbidity and mortality for these patients.⁶² Coronary artery disease may result from coronary arteritis or thrombosis, but is most often secondary to atherosclerosis. Making a diagnosis of coronary arteritis is challenging owing to the nonspecificity of the angiographic findings. It may require sequential angiographic studies showing changes in luminal blockages over time not expected with atherosclerosis. Coronary arteritis, if suspected, may be treated with high doses of corticosteroids, possibly in combination with another potent immunosuppressive agent, such as cyclophosphamide. Coronary thrombosis may be associated with the presence of antiphospholipid antibodies (see next section) or embolism from a valvular vegetation, as seen in Libman-Sacks endocarditis.

Recent data suggest that subclinical atherosclerosis is highly prevalent amongst SLE patients.⁶² Women with SLE between the ages of 35 and 44 years are 50 times more likely to have a myocardial infarction than are those without SLE.⁶³ Young women with SLE may have several risk factors for coronary atherosclerosis, such as hypertension, which may be secondary to renal disease and diabetes brought about or worsened by corticosteroid exposure. In epidemiologic studies, SLE has been shown to be an independent risk factor for cardiovascular disease, and this is supported with basic science data.⁶¹ However, the mechanisms underlying this predisposition are unclear, and their relationship to the systemic inflammatory response in SLE remains an area of investigation. Recently, patients with SLE have been shown to produce proinflammatory forms of high-density lipoprotein that confer an increased risk for atherosclerosis.⁶⁴ It is important to recognize that because SLE is predominately a disease of young women, and this group is at increased risk for coronary artery disease, prompt evaluation is warranted if they develop any symptoms of cardiac ischemia.

Drug-Induced Lupus

Drug-induced SLE (DIL) may be a rare complication of certain medications, including procainamide, quinidine, and hydralazine. Other medications associated with DIL include isoniazid, minocycline, clindamycin, and phenytoin. DIL, which affects males and females equally, is associated with the development of serum anti-histone antibodies, although only a few patients will actually develop the clinical syndrome. Common signs and symptoms of DIL include pericarditis, pleuritis, arthralgia, and fever. It is rare to develop renal or neurologic complications from DIL. The syndrome will usually resolve on its own after a short course of prednisone and discontinuation of the offending medication.⁶⁵

Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a disorder characterized by the clinical triad of recurrent arterial or venous thromboses, pregnancy loss, and thrombocytopenia. Serologically, it is defined by the presence of anticardiolipin antibodies, anti-β₂ glycoprotein antibodies, or a positive lupus anticoagulant. APS may occur independently (primary APS) or in association with SLE or other autoimmune disease (secondary APS).

Because APS may produce thrombotic occlusion of many different types and sizes of blood vessels, it can produce a variety of cardiovascular manifestations. Valvular disease is the most common APS-related cardiovascular manifestation. It is seen in both primary and secondary APS, and is essentially indistinguishable from Libman-Sacks endocarditis. Patients with asymptomatic valvular thickening should be treated with a low-dose daily aspirin (81 mg); however, those with evidence of vegetation or embolization should be treated with systemic anticoagulation (target INR 2-3).⁶⁶ Coronary artery disease and accelerated atherosclerosis have also been associated with APS, although it seems that all types of antiphospholipid antibodies do not equally contribute to atherosclerosis. In a study by Soltész and colleagues,⁶⁷ presence of lupus anticoagulant was more frequently associated with venous thrombosis, whereas anticardiolipin antibodies were more often associated with carotid, peripheral, and coronary artery disease. The link between myocardial infarction and APS is less certain. Although some studies have shown a positive correlation between serum antiphospholipid antibodies and myocardial infarction,^68,69 other large cohorts have not found this relationship.⁷⁰ Patients with a history of myocardial infarction should have aggressive treatment of all risk factors for atherosclerosis and be placed on statin therapy.⁶⁶ Intracardiac thrombi, cardiomyopathy, and pulmonary hypertension have also been associated with APS.⁷¹ Overall, the immunosuppressive and antithrombotic management of APS has been somewhat controversial. Recent guidelines have agreed, however, that patients with definite APS and a first venous event receive oral anticoagulant therapy to a target INR of 2.0 to 3.0, grading this as a IA recommendation.⁷² Other multidisciplinary task force recommendations agree, also assigning a grade of IA.⁷³

Dermatomyositis and Polymyositis

Dermatomyositis (DM) and polymyositis (PM) are two inflammatory muscle diseases in which there may be cardiovascular manifestations. Patients with DM usually present with skin involvement characterized by erythematous scaliness over the knuckles (Gottron papules), elbows, and knees, as well as periorbital swelling and a violaceous rash around the lids, known as a heliotropic rash. They may also display a photosensitive rash over the face, chest, and back in a shawl-like distribution. Both DM and PM are manifested by proximal muscle weakness and most affected individuals show increases in serum levels of muscle enzymes such as creatine kinase and aldolase. Although the pathophysiology of DM and PM is incompletely understood, these diseases are associated with a specific set of serum autoantibodies, including antiaminoacyl-tRNA synthetase (antihistidyl-tRNA synthetase and others), antisignal recognition particle, and anti-SNF2 superfamily nuclear helicase (anti-Mi-2). The histopathology of the muscle lesions is different in the two diseases. DM is characterized by a mixed T- and B-cell perivascular infiltrate with perifascicular atrophy. By contrast, muscle biopsies from patients with PM show a predominance of T cells and a diffuse or patchy inflammation of the muscle fascicles. DM may also be associated with a systemic angiopathy. In older patients, DM and PM may evolve as a paraneoplastic syndrome. Although these diseases primarily affect striated muscle, they may also cause cardiovascular complications.

Cardiovascular complications of DM/PM include pericarditis, conduction system abnormalities, heart failure, and myocarditis. Pericardial involvement has been noted most often in patients with overlap syndromes (ie, features of two or more connective tissue diseases). Conduction abnormalities, nonspecific ST-T changes, and LV diastolic dysfunction have also been reported in DM/PM.⁷⁴ A serious cardiovascular complication is myocardial infarction secondary to coronary vasculitis.⁷⁵ Myocarditis may infrequently cause heart failure, although newer imaging modalities, particularly cardiac MRI with gadolinium enhancement, may detect subclinical disease in as many as one-half of patients with DM/PM and be useful in monitoring response to therapy.⁷⁶

It is important to rule out other forms of myopathy in patients who present with muscle weakness. Patients taking statins may develop a myopathy mimicking inflammatory muscle disease. Statin-related myopathy and inflammatory myopathy may be differentiated by certain aspects of the medical history (eg, statins usually associated with significant myalgia), the results of electromyography, and findings on muscle biopsy, if necessary. For statin-induced myopathy, withdrawal of the offending drug will lead to symptom resolution. The cornerstone of the treatment for DM/PM is high doses of corticosteroids, usually in doses of 1 mg/kg for several months with a slow taper. Adjunctive therapy often includes methotrexate or azathioprine. Intravenous immunoglobulin may be effective for treating refractory and severe cases.

Systemic Sclerosis

Systemic sclerosis (or scleroderma) is a rare disorder characterized by microvascular injury and excessive fibrotic changes that can affect multiple organ systems. Most commonly, systemic sclerosis causes hardening of the skin, but can also affect visceral organs, such as lungs, kidneys, and the heart. The diffuse or progressive type of systemic sclerosis results in widespread cutaneous involvement of the distal and proximal extremities as well as the trunk, and is usually associated with early and serious visceral involvement. In contrast, limited cutaneous systemic sclerosis, also known as CREST syndrome, is characterized by calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias. Systemic sclerosis may be associated with late involvement of visceral organs, especially increased risk for pulmonary artery hypertension (PAH). Cardiovascular involvement of systemic sclerosis may occur with either the diffuse or limited forms, as well as overlap syndromes in which patients may have features of systemic sclerosis in combination with those of SLE, RA, or polymyositis.

Pericardial Disease

Pericardial disease in systemic sclerosis is usually benign. On the basis of autopsy results, the incidence of pericardial involvement is approximately 50%, but symptomatic pericarditis only manifests in approximately 16% of patients with diffuse scleroderma and in approximately 30% of patients with limited scleroderma.⁷⁷ Pericardial effusions rarely cause symptoms, although they can be detected in approximately 40% of patients by echocardiography. In most cases, the effusion is relatively small and of no clinical consequence. Routine pericardiocentesis in the absence of cardiac tamponade has no apparent effect on clinical outcomes.⁷⁷ Pericardial involvement can present either as acute pericarditis associated with dyspnea, chest pain, and pericardial friction rub, or as a chronic pericardial effusion leading to constrictive physiology. For the treatment of acute pericarditis, nonsteroidal anti-inflammatory therapy is recommended, provided renal function is unaffected. Pericardiocentesis or surgical intervention is considered only if pericarditis is complicated by tamponade or constriction or if acute infection is suspected. Corticosteroids are generally considered to be of limited benefit, but they may be lifesaving in the setting of associated myocarditis.

Myocardial Disease

Although interstitial lung disease (ILD) and PAH are the most common cardiopulmonary conditions that result in increased morbidity and mortality, other cardiac complications may occur. In one study, echocardiographic findings were analyzed over more than 5 years from 77 unselected patients with systemic sclerosis and compared with those from 45 normal subjects matched for age and sex.⁷⁸ At baseline, LV systolic function was normal in both patients and controls, whereas LV diastolic function was found to be more prevalent in the patients compared with the controls (23 vs 1; P < .001). By the end of the follow-up period (~2-8 years), LV systolic dysfunction had developed in one patient, and diastolic dysfunction was documented in another six patients. Moreover, in the group with systemic sclerosis, diastolic dysfunction, left atrial dimension, and LV wall thickness significantly progressed over the course of the observation period. The change in LV diastolic function was independent of other factors, including LV hypertrophy, systemic hypertension, age, and duration of disease, all of which could potentially affect LV relaxation. These results confirm that LV diastolic dysfunction is a frequent manifestation of systemic sclerosis.⁷⁸ Although diastolic dysfunction is common in this disease, it is rarely severe. When severe, diastolic dysfunction may worsen PAH.

Arrhythmias and Conduction System Disturbances

The most frequent cardiac rhythm disturbance is premature ventricular contractions, often appearing as monomorphic, single ectopic events, or rarely as bigeminy, trigeminy, or couplets.⁷⁹ Transient atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia have been reported in 20% to 30% of patients with systemic sclerosis. Nonsustained ventricular tachycardia has been described in 7% to 13%, whereas sudden cardiac death has been reported in 5% to 21% of unselected patients with systemic sclerosis. Conduction disturbances occur in 25% to 75% of patients. Although conduction abnormalities are mostly due to fibrosis in the sinoatrial node, direct involvement of the cardiac conduction tissue also occurs, leading to disturbances such as bundle and fascicular blocks.⁷⁶

Pulmonary Arterial Hypertension

PAH is another serious cardiopulmonary complication of systemic sclerosis. It is included in the first group of the World Health Organization classification of pulmonary hypertension, characterized by precapillary pulmonary hypertension with pulmonary capillary wedge pressure ≤ 15 mm Hg.⁸⁰ Primary pulmonary arteriopathy occurs most commonly in patients with the limited cutaneous form of systemic sclerosis. Although at autopsy 65% to 80% of patients with systemic sclerosis have histopathologic changes consistent with PAH, fewer than 10% develop clinically apparent disease.⁸¹ PAH should always be considered in the setting of dyspnea or right-heart failure in patients with systemic sclerosis. Patients with PAH associated with systemic sclerosis appear to have a worse prognosis than patients with idiopathic PAH, showing an untreated 2-year survival rate as low as 40%.⁸² Although there are an increasing number of clinical trials demonstrating the benefit of available PAH specific therapy (described later) and likely improvement in prognosis,⁸³ patients with scleroderma-related PAH still have a less favorable outcome than those with idiopathic PAH.⁸⁴

The three main categories of medications used to treatment PAH include prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type-5 inhibitors. Randomized clinical trials in patients with PAH have often included PAH associated with systemic sclerosis and, as such, have led to approval by the US Food and Drug Administration of a number of agents for this patient population. The largest prospective, randomized trial to date that has focused on PAH in systemic sclerosis was a study of 111 patients with moderate-to-severe pulmonary hypertension.⁸⁶ It demonstrated that continuous intravenous epoprostenol therapy delivered over 12 weeks improved exercise capacity and cardiopulmonary hemodynamics. Newer agents like selexipag, a non-prostanoid oral IP receptor agonist, and riociguat, a soluble guanine cyclase receptor agonist, are also now approved for PAH associated with systemic sclerosis.^87,89 Improvement has been shown using the standard 6-minute walk test, although some studies have shown benefit in pulmonary hemodynamics and quality of life.

Although lung or heart-lung transplantation has been performed in patients with ILD or severe PAH due to systemic sclerosis, this approach has been somewhat controversial. Several studies suggest that outcomes of patients with systemic sclerosis undergoing lung transplant were not significantly different from those of patients transplanted for other lung conditions during the same period.^88,90 Gastrointestinal dysmotility and associated gastroesophageal reflux are substantial concerns, as aspiration has been associated with chronic allograft rejection.⁹¹ Unfortunately, patients with systemic sclerosis and PAH or ILD that might be severe enough for transplant commonly have multiple morbidities that render them less than ideal lung transplant candidates.

Finally, it is important that cardiopulmonary rehabilitation be considered in appropriately selected patients with systemic sclerosis and associated cardiopulmonary disease.⁸⁵ Caution is important with advanced pulmonary hypertension and syncope, as such patients should refrain from intensive rehabilitation.

Seronegative Spondyloarthropathies

The seronegative spondyloarthropathies (characterized by the absence of serum rheumatoid factor) are a group of multisystem inflammatory diseases sharing common features, including spinal or sacroiliac involvement, enthesitis (inflammation at the sites where tendons and ligaments insert onto bones), and a high incidence of HLA-B27. Among this group of related diseases are ankylosing spondylitis, reactive arthritis (previously referred to as Reiter syndrome), psoriatic arthritis, and inflammatory bowel disease–associated arthritis. In the United States, up to 10% of healthy Caucasians are positive for HLA-B27; the incidence is much lower in African Americans and Asians. HLA-B27 is most strongly associated with ankylosing spondylitis in Caucasians, occurring in 90% of patients with this disorder. Although most patients with ankylosing spondylitis will test positive for HLA-B27, it should be noted that the majority of patients with HLA-B27 do not have a spondyloarthropathy. A medical history and examination indicative of inflammatory spinal disease and enthesitis and typical radiographic findings form the basis for diagnosis after excluding other forms of inflammatory arthritis, such as RA. In contrast to RA, the spondyloarthropathies occur more commonly in males than females and do not usually involve the small joints of the hands in a symmetrical pattern. Peripheral arthritis tends to involve larger, usually lower-extremity, joints in an asymmetric distribution.

Among the group of spondyloarthropathies, ankylosing spondylitis and reactive arthritis are the most frequently associated with cardiovascular manifestations. The two most prevalent cardiovascular manifestations of the spondyloarthropathies are conduction system disease and aortitis, with or without aortic insufficiency. The conduction system disease presents mainly as atrioventricular block, which occurs more commonly in males that are HLA-B27 positive than in females; it often requires permanent pacemaker placement. Electrophysiologic studies reveal the block to be at the level of the atrioventricular node; it is usually not fascicular.⁹² Aortic root involvement is also associated with HLA-B27 in patients with ankylosing spondylitis⁹³ and reactive arthritis.⁹⁴ Aortitis may lead to dilatation and stiffening of the aortic root with aortic valvular regurgitation. Aortic valvular regurgitation is usually a late complication of the spondyloarthropathies.⁸⁶ Other less common cardiac manifestations associated with spondyloarthropathies include clinically insignificant diastolic dysfunction, supraventricular tachycardias (especially atrial fibrillation),⁹² myocarditis, and pericarditis.

Treatment of the spondyloarthropathies was previously limited to nonsteroidal anti-inflammatory drug therapy and physical therapy. More recent studies clearly demonstrate the clinical efficacy of TNFα inhibitors for treating symptoms of spondylitis. It is unknown whether the TNFα inhibitors will ameliorate cardiovascular manifestations of the spondyloarthropathies. Surgery has been successful for managing severe aortic regurgitation associated with ankylosing spondylitis.⁹⁵

Systemic Vasculitides

The systemic vasculitides are multisystem diseases whose hallmark is inflammation of blood vessels (Table 100–2). Categorization of these diseases is based on the size of vessel involved (small, medium, and large) and the nature of organ system involvement. Vasculitis may be primary or secondary (eg, identifiable trigger such as a drug or infection). Primary vasculitides are presumably due to immune dysregulation in which genetic factors and environmental insults may play roles in their pathogenesis.

Giant-Cell (Temporal) Arteritis

Giant-cell arteritis (GCA), also known as temporal arteritis, is the most common vasculitis among patients older than 50 years.⁹⁶ It is more common in women than in men and seems to be more prevalent in persons of Northern European descent than African Americans. The clinical hallmarks of GCA are temporal artery tenderness, headache, jaw claudication, and visual loss. Many patients also manifest constitutional symptoms, such as fatigue and fever, and approximately one-third of cases are associated with polymyalgia rheumatica. Almost all patients with GCA have an elevated erythrocyte sedimentation rate (usually exceeding 50 mm/h) and serum C-reactive protein level. Temporal artery biopsy, the gold standard for diagnosis, shows evidence of transmural chronic granulomatous inflammation with destruction of elastic laminae. Negative biopsy results may indicate that the biopsy missed the area of vascular pathology (sampling error due to skip lesions), the biopsy was done on the wrong temporal artery (unilateral biopsy), the sample was too small (< 2 cm), or the patient does not have GCA. The disease may also target the extracranial large artery branches of the aortic arch. Peripheral artery involvement has become increasingly recognized as a complication of GCA and may be the presenting feature of this disease. Signs and symptoms of peripheral large artery involvement include intermittent upper-extremity claudication, decreased or absent peripheral pulses, and bruits over affected vessels.

GCA may also lead to thoracic and abdominal aortic aneurysm. In one study, 16 of 41 patients with GCA and aortic aneurysm had an acute aortic dissection, with 8 deaths.⁹⁷ Given these findings, it has been recommended that patients with GCA undergo yearly screening for aortic aneurysm using transthoracic echocardiography and abdominal ultrasonography.⁹⁸ Other cardiovascular complications rarely associated with GCA are pericarditis, myocarditis, and coronary arteritis.⁹⁹

Although temporal artery biopsy remains the diagnostic gold standard for GCA, advances in imaging techniques have provided new diagnostic tools for assessing patients with this disease. A noninvasive approach for detecting vasculitis of the temporal arteries is duplex ultrasonography. Ultrasonography of involved temporal arteries demonstrates segmental, concentric hypoechogenic thickening of the arterial wall (“halo sign”). Sonography can also be important in diagnosis, assessment, and follow-up of peripheral artery disease.¹⁰⁰ Computed tomography (CT) angiography and magnetic resonance angiography (MRA) have the added capability of detecting mural inflammation, aneurysms, and luminal narrowing¹⁰¹ (Fig. 100–3). Although both CT angiography and MRI/MRA can provide excellent vascular detail, MRI/MRA does not expose the patient to ionizing radiation. Additionally, further information can be ascertained by MRI/MRA about the extent of arterial wall edema using gadolinium enhancement. Because arterial wall edema may correlate with the degree of vessel inflammation, MRI may be more useful than ultrasound for evaluating the extent of vessel inflammation and, therefore, may be superior for monitoring treatment response.¹⁰² Finally, in recent studies, fluorine-18-deoxyglucose (FDG) positron emission tomography has been shown to be useful for detection of large-vessel vasculitis.¹⁰³ It is a whole-body scan that reportedly can detect arteritis at very early stages, and although it holds some promise, its use is still restricted by high costs and the relatively high radiation exposure.¹⁰¹ Additionally, atherosclerosis can also increase uptake of FDG in the larger vessels, raising some problems with diagnostic specificity.

Corticosteroids are the mainstay of therapy for GCA. High doses of prednisone (0.7-1 mg/kg/d) are employed initially and are then tapered slowly, depending on clinical improvement and the decrease in serum levels of acute phase reactants. Many patients with GCA do not achieve remission with high doses of prednisone and require long-term maintenance with prednisone in low doses. Other immunosuppressive agents, such as methotrexate, may be combined with prednisone, but the evidence supporting their clinical efficacy in this situation remains conflicting.¹⁰⁴ Controlled trials have failed to establish a role for TNFα inhibitors in the treatment of GCA.¹⁰⁵ However, in a case-control study, the addition of a low dose of aspirin reduced the rate of blindness and stroke in patients with GCA by three- to fourfold compared with those patients who did not receive aspirin.^106,107 In the absence of any contraindications, low-dose aspirin should be given to all patients with GCA.

Takayasu Arteritis

Takayasu arteritis (TA) is another large-vessel vasculitis that histologically is indistinguishable from GCA, but occurs preferentially in young women. It tends to affect the aorta and its major branches. It is a rare disease in the United States, with an estimated incidence in one study of 2.6 cases per million per year.¹⁰⁸ However, it is more common in women of Japanese, Indian, and African descent. Classically, clinical presentation begins with systemic manifestations such as fever, malaise, weight loss, arthralgias, and myalgias. Arterial stenoses are more common than aneurysms and, therefore, the most common signs and symptoms are those of arterial occlusion, including “pulselessness,” claudication, headaches, and chest pain. TA is often associated with hypertension, often secondary to renal artery stenosis, although this finding may be missed because subclavian stenosis may cause falsely low peripheral blood pressure readings. Aneurysms may also develop secondary to large-vessel involvement, most commonly in the aortic root.

Diagnosis of TA is usually based on the results of vascular imaging studies that show a pattern of vascular involvement typical of this disease. Most patients with TA have elevated serum levels of acute-phase reactants, reflecting the systemic nature of the inflammatory response. Biopsies are not usually obtained for diagnosis because of the inaccessibility of the affected tissue. For the treatment of TA, patients usually receive initial dosing of prednisone at 1 mg/kg/d. Relapses are common when the steroids are tapered. If patients are refractory to corticosteroid therapy, then methotrexate or cyclophosphamide may be considered as an adjunctive immunosuppressive drug or steroid-sparing agent. The progression of disease may be monitored by repeat testing of acute-phase reactant levels and serial imaging studies, such as CT angiography or MRI/MRA (Fig. 100–4). However, normalization of acute-phase reactant levels does not necessarily exclude progression of vascular disease. Patients with TA frequently require vascular bypass surgery to correct clinically significant stenosis, especially in the setting of transient ischemic attacks and renal artery stenosis with hypertension. More recently, endovascular stents have been used in patients with chronic inactive TA lesions and appear to be associated with a good outcome.¹⁰⁹ Finally, aortic valve replacement may be necessary in patients with aortitis and severe aortic regurgitation.

Kawasaki Disease

Kawasaki disease is an acute febrile illness affecting children from ages 6 months to 8 years. In the United States, its annual incidence is approximately 6 per 100,000 children younger than 5 years, occurring, in order of decreasing frequency, in children of Asian, African American, and Caucasian race. Although the etiology of this disease is unknown, epidemiologic studies have highlighted the geographic clustering of Kawasaki disease cases and, therefore, it is speculated that this disease may be triggered by an infectious agent. The affected child presents with fever, desquamative rash, conjunctivitis, and lymphadenopathy.

During this acute phase of Kawasaki disease, the cardiovascular system may be affected in various ways. Pericarditis, myocarditis, mitral regurgitation, aortitis, aortic regurgitation, congestive heart failure, and arrhythmias have all been described in this illness.¹¹⁰ Coronary vasculitis develops in as short a time as 2 weeks after symptom onset, but usually within 4 weeks after the onset of fever. If left untreated, this process may lead to the development of coronary aneurysms, the most serious complication of this disease.¹¹¹ Aneurysms measuring larger than 8 mm by echocardiography, termed giant aneurysms, are the most likely to thrombose and cause myocardial infarction. These giant aneurysms are also the least likely to regress with therapy.

Clinical studies of Kawasaki disease have shown that treatment with intravenous immunoglobulin and aspirin reduces the development and progression of coronary aneurysms.¹¹² Intravenous immunoglobulin is given at 2 g/kg as a single infusion, whereas aspirin is administered at 80 to 100 mg/kg/d.¹¹³ The American Heart Association recommends long-term follow-up of children with multiple giant aneurysms or known obstructive lesions because of the risk for further cardiac complications. Management for these patients includes chronic low-dose aspirin therapy, stress testing in adolescence, and coronary artery bypass or percutaneous intervention if lesions are severe enough to be symptomatic.¹¹⁴

Wegener Granulomatosis

Wegener granulomatosis (WG) is a systemic necrotizing vasculitis of small vessels mainly targeting the respiratory tract and the kidneys. Upper respiratory involvement may consist of pansinusitis, nasal blood discharge, oral ulcers, and subglottic stenosis. Symptoms of lung involvement are cough, dyspnea, and hemoptysis. The chest x-ray may show pulmonary nodules with or without cavitation, transient infiltrates, or evidence of alveolar hemorrhage. Glomerulonephritis is a harbinger of poor outcomes. Renal biopsy reveals the classic features of a pauci-immune, focal, segmental necrotizing glomerulonephritis. The laboratory hallmark of WG is the presence of serum antineutrophil cytoplasmic antibodies (ANCA). There are two predominant ANCA patterns: C-ANCA and P-ANCA, which are associated with serum antibodies to proteinase-3 and myeloperoxidase, respectively. WG is predominately associated with anti–proteinase-3 antibodies, but a minority of patients with this disease have anti-myeloperoxidase antibodies. It is important to recognize that serum ANCA may be absent in some patients with WG, especially those with less severe forms of the disease.

In one study, cardiac involvement, including cardiomyopathy, pericarditis, and coronary arteritis, was described in 6% of 158 patients with WG.¹¹⁵ Additionally, there have been case reports of aortic regurgitation and high-grade atrioventricular block. A recent study also suggested that patients with WG are at a significantly increased risk for complications of ischemic heart disease.¹¹⁶

Overall, the prognosis for severe WG has improved with the use of corticosteroid therapy combined with daily oral cyclophosphamide.¹¹⁵ Studies also support the use of methotrexate combined with oral prednisone for treatment of patients with non–life-threatening WG.¹¹⁷ Surgical valve replacement and pericardiectomy have been performed for hemodynamically or clinically significant valvular disease or constrictive pericarditis, respectively.^118,119

Churg-Strauss Syndrome

Churg-Strauss syndrome (CSS) is a relatively rare type of systemic vasculitis characterized by asthma, peripheral eosinophilia, and radiographic evidence of pulmonary infiltrates usually secondary to pulmonary vasculitis. Histopathologic lesions usually reveal a small- and medium-sized vessel vasculitis with eosinophilic granulomas, distinguishing CSS from the medium-sized vessel vasculitis called polyarteritis nodosa. Other target organs of CSS include the kidneys, central nervous system, skin, and heart.

Heart disease is particularly prominent in CSS, with involvement of the cardiovascular system in up to 60% of cases; more importantly, it is the most common cause of death in these patients.¹²⁰ The pathophysiology for the development of cardiac disease has not been elucidated, and it is unclear whether manifestations such as cardiomyopathy are a result of small-vessel vasculitis, eosinophilic infiltration of the myocardium leading to fibrosis, or a combination of both processes. Pericardial effusion, myocardial infarction, and myocarditis have also been reported in patients with CSS. Treatment of CSS with corticosteroids is usually very effective in the early stages of disease, although critically ill patients usually require treatment with a second immunosuppressive agent, such as cyclophosphamide. Patients with severe cardiomyopathy have undergone heart transplant with mixed results.¹²¹

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is another relatively rare vasculitis that predominately affects the medium-sized arteries without granuloma formation. The evolution of the nosology of the systemic vasculitides has led to some recent confusion between the classification of PAN and microscopic polyangiitis (MPA). Patients with small-vessel involvement, such as pulmonary capillaritis or glomerulonephritis, are now deemed to have MPA and not classic PAN, and therefore many older studies of PAN have included patients with both classic PAN and MPA. The clinical presentation of PAN varies according to the affected organ system. Common manifestations include painful nodules on the skin, neuropathy in the form of a mononeuritis multiplex, gastrointestinal vasculitis with abdominal pain, and hypertension; characteristically, the lungs are spared.¹²²

Cardiovascular complications of PAN have been reported in approximately 10% of patients in clinical studies and up to 78% in a histologic study.¹²⁰ The most common cardiovascular manifestations are heart failure, angina, myocardial infarction, and pericarditis. Various arrhythmias, mainly supraventricular tachycardias, have been associated with PAN, as well as hypertension from renal involvement. Treatment of PAN is similar to that of CSS and the other systemic necrotizing vasculitides. High-dose corticosteroids are the mainstay for initial treatment, with the addition of cytotoxic agents such as cyclophosphamide in severe cases. Overall, PAN is considered a more severe disease than CSS, with a higher incidence of mortality.¹²³

Behçet Disease

Behçet disease is rare in the United States, but is prevalent in the countries bordering the Mediterranean and in Japan. Behçet disease consists of the clinical triad of oral and genital ulcerations as well as recurrent uveitis. Patients with Behçet disease may also develop vasculitis affecting blood vessels of different sizes, including the small-, medium-, and large-sized vessels.¹²⁴ Medium and large artery lesions are often aneurysmal. In addition, patients with Behçet disease are at risk of developing thrombosis of the deep veins of the lower extremities. Cases have been described of occlusive and aneurysmal lesions of the coronary arteries that have led to myocardial infarction.^125,126 Treatment of Behçet relies mainly on corticosteroids as well other immunomodulatory agents, such as methotrexate or azathioprine. Chronic anticoagulation is recommended for patients with recurrent thromboses.

The connective tissue diseases are a group of heritable conditions that can affect skin, joints, and vasculature. The following section reviews the most common connective tissue diseases that affect the cardiovascular system (Table 100–3).

Marfan Syndrome

Marfan syndrome is among the most prevalent of the heritable connective tissue diseases, with an estimated worldwide prevalence of 1 per 3000 to 5000 persons.¹²⁷ Although up to one-third of patients have no family history of Marfan syndrome, most cases are inherited as a result of a high penetrance of an autosomal-dominant mutation in the fibrillin (FBN1) gene. More than 1000 mutations in the FBN1 gene have been identified to date. Marfan patients often have a tall stature, long extremities, high-arched palate, joint hypermobility, and ectopia lentis. Additionally, they can have musculoskeletal abnormalities including a pectus excavatum or carinatum chest deformity or scoliosis. Because some of these features are present in the general population, there has been increased attention given to improving the classification of this disease. The 2010 Ghent criteria place emphasis on aortic root dilatation, aortic dissection, and ectopia lentis as cardinal clinical features of Marfan syndrome and on testing for mutations in the FBN1 gene.¹²⁸

The complications of Marfan syndrome with potential lethality involve the cardiovascular system. Such patients may develop dilatation of the proximal ascending aorta, dilatation of the proximal pulmonary artery, mitral valve prolapse, and cardiomyopathy. The fibrillin gene encodes proteins essential for the proper formation of microfibrils that uphold the integrity of the extracellular matrix. Patients with Marfan syndrome who have mutations in these genes produce a “weak collagen” in the arterial walls. In the aorta, these changes reduce vessel distensibility and increase wall stiffness. These effects, coupled with the hemodynamic stress in high-flow areas, over time lead to the development of aneurysms, which can be complicated by intimal dissection. Aortic root dilatation causes stretch of the aortic valve, which may lead to aortic valve regurgitation. Mitral valve prolapse is also commonly associated with Marfan syndrome and occurs in up to one-quarter of patients. It may lead to mitral regurgitation, which if severe and uncorrected, can result in a dilated cardiomyopathy.¹²⁹ Cardiomyopathy in the absence of valvular disease has also been reported in patients with Marfan syndrome and is believed to be secondary to defective cardiac muscle function from fibrillin mutations.¹³⁰

Life expectancy has significantly improved with proper identification and monitoring of patients with Marfan syndrome. The most common causes of death in these patients are rupture of an ascending aortic aneurysm with or without dissection or heart failure from aortic or mitral regurgitation. It is important that Marfan patients be counseled to avoid isometric or strenuous exercise, including contact sports (Table 100–4).

It is currently recommended that all Marfan patients receive the maximum-tolerated dose of a β-blocker. The beneficial effects of β-blockade are reduction in heart rate and in the rate of pressure increase in the aorta, which leads to less cumulative stress on the aorta.¹³¹ Additionally, β-blockers have demonstrated to both decrease the rate dilatation of the ascending aorta and to improve survival.¹³² The addition of an angiotensin-converting enzyme should also be considered in this patient population. In a large prospective randomized trial of 233 patients with Marfan syndrome, the addition of losartan slowed aortic root enlargement.¹³³

Patients with Marfan syndrome should undergo annual echocardiography. Recommendations vary with respect to the optimal time for prophylactic surgical intervention. The most recent guidelines recommend prophylactic surgery in patients with an aortic diameter of 5.0 cm or more, or in those with a diameter of 4.5 cm and one of the following: experiencing severe aortic valve regurgitation, undergoing aortic valve replacement, or having a family history of complications. Those with an annual growth rate of greater than 0.5 cm are also considered for prophylactic surgery.¹³⁴ After surgical intervention, yearly MRI or CT scan is recommended to monitor the graft.

Finally, female Marfan patients of child-bearing age should be counseled regarding the relatively high risk of transmission of their disease to their offspring. Further, if a woman already has aortic root dilatation greater than 40 mm, pregnancy should be avoided due to the high risk of complications when systemic blood pressure is increased during delivery. If the aortic root is less than 40 mm, pregnancy need not be avoided. However, the woman must be carefully monitored during pregnancy with monthly or bimonthly transthoracic echocardiograms and have strict blood pressure goals to prevent stage II hypertension.¹³⁴

Loeys-Dietz Syndrome

Loeys-Dietz types I and II are among the more recently recognized of the heritable connective tissue diseases; their associated mutations reside in the genes encoding the transforming growth factor β receptors 1 and 2.¹³⁵ Although these patients were previously categorized as having either Marfan syndrome or Ehlers-Danlos syndrome of the vascular type, more sophisticated molecular analysis has led to disease reclassification. Similar to patients with Marfan syndrome, these patients may have aortic aneurysms and musculoskeletal abnormalities such as scoliosis or pectus excavatum. However, patients with type I Loeys-Dietz also display the clinical triad of hypertelorism, either bifid uvula or cleft palate, or both, and generalized vascular aneurysms. The type II patients are characterized by cutaneous manifestations such as velvety translucent skin, easy bruising, and widened atrophic scars that are also seen in patients with Ehlers-Danlos vascular type. Loeys et al¹³⁵ studied 52 affected families and found that patients with Loeys-Dietz type I had shorter lives and underwent cardiovascular surgery earlier than type II patients. There was rapid formation of arterial aneurysms and a high incidence of pregnancy-related complications in both types. Distinguishing patients with Loeys-Dietz syndrome and transforming growth factor β receptor mutations from patients with Marfan syndrome and Ehlers-Danlos syndrome is important for guiding medical therapy, making decisions about the optimal timing of prophylactic surgery, and management of pregnancy. Aortic disease appears to be more aggressive in patients with Loeys-Dietz disease.¹³⁶ Current criteria for elective intervention for asymptomatic aneurysms in adults with Loeys-Dietz syndrome include an aortic diameter > 4.2 cm by transesophageal echocardiography (internal diameter) or 4.4 to 4.6 cm or greater by CT and/or MRI (external diameter), and/or rapid expansion (> 0.5 cm/yr).^134,136

Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome comprises a group of disorders that are characterized by hyperextensibility of skin, easy bruising, and joint hypermobility. There are six clinical types of Ehlers-Danlos syndrome; the vascular type, or type IV, is associated with mutations of the COL3A1 gene. Its prevalence is estimated to be 1 case per 100,000 to 250,000 persons and this subtype primarily affects the cardiovascular system.¹³⁷ Ehlers-Danlos of the vascular type, which can mimic Loeys-Dietz syndrome, leads to diffuse vascular aneurysms (including the thoracic and abdominal arteries) that have a tendency for spontaneous rupture. Although prophylactic surgery for thoracic aortic aneurysms for Loeys-Dietz and Marfan syndrome is well established, its role in Ehlers-Danlos is not clear. This is likely due to tissue fragility, a tendency to hemorrhage extensively, and poor wound healing that may complicate the surgical repair.¹³⁴ Approximately one in four people with vascular type Ehlers-Danlos syndrome develop morbidity by 20 years of age, and more than 80% develop life-threatening complications by 40 years of age.¹³⁸ Pregnant women must receive care from a team of specialists familiar with high-risk situations because of the propensity for vascular complications and uterine rupture.

Familial Thoracic Aortic Aneurysms and Dissections

Familial thoracic aortic aneurysms and dissections are autosomal dominant diseases that account for approximately 20% of thoracic aortic aneurysms and dissections.¹³⁹ Although several gene mutations have been linked to this disease, the ACTA2 gene mutation is the most common, accounting for approximately 14% to 20% of cases.¹⁴⁰ Mutation in ACTA2 primarily affects the function of sarcomeres found in the vascular smooth muscle in the walls of the aorta. The sarcomeres lose the ability to prevent the aorta from stretching as blood courses through. As a result, patients develop aortic root dilatation, aneurysms, and eventual dissections. The second most common gene mutation is the TGFBR2, which interestingly is the same gene that is mutated in approximately two-thirds of patients with Loeys-Dietz syndrome. And much like Loeys-Dietz disease, aortic dissections occur in patients with TGFBR2 mutation at diameters less than 5.0 cm, leading to the recommendation that aortic repair be considered at an internal diameter by echocardiography of 4.2 cm or greater.¹³⁴ Other gene mutations include FBN1, TGFBR1, COL3A1, and MYH11. If a mutant gene is identified in a patient, first-degree relatives should undergo counseling and testing. Then, only the relatives with the genetic mutation should undergo aortic imaging. ¹³⁴

Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum is a rare disorder with an estimated prevalence of between 1 in 25,000 and 1 in 100,000 persons that can be transmitted either as an autosomal dominant or recessive trait.¹⁴¹ It is characterized by progressive accumulation of mineral precipitants within elastic fibers of the skin, eyes, gastrointestinal tract, and blood vessels. Clinically, patients display yellow macules or papules on their skin that have a cobblestone appearance at areas where there is flexion, such as the axillae, groin, and popliteal spaces. They also develop angioid streaks on the retina that represent breaks in Bruch’s membrane behind the eye. Mutations in the gene ABCC6 (R1141X) have been implicated in the development of this disease, as well as in the increased risk for developing coronary artery disease in this setting.¹⁴² The vascular manifestations of the disease are secondary to degeneration of the elastic lamina of blood vessels and subsequent development of calcifications. Clinical manifestations are angina, claudication, and gastrointestinal bleeding.

Echocardiography of affected patients may reveal calcification of the atrial and ventricular endocardium, valves, and calcified thrombi, which can result in mitral valve prolapse, mitral valve stenosis, or restrictive cardiomyopathy.¹⁴³ Surgery has been used to remove these calcium deposits, but otherwise, management involves proper identification of affected patients, strategies to reduce the propensity for bleeding, and intensive management of blood cholesterol levels.

Osteogenesis Imperfecta

Another heritable connective tissue disease is osteogenesis imperfecta, also known as brittle bone disease. Individuals with this rare condition are susceptible to skeletal fractures from mild trauma. The disease occurs secondary to mutations in type 1 collagen, producing disease of varying clinical severity ranging from severe phenotypes that cause death in utero to mild phenotypes that may remain undetected until adulthood. Typical manifestations include blue sclerae, hearing loss, easy bruising, and increased risk of bleeding. Cardiovascular manifestations consist of aortic regurgitation, aortic root dilatations, aortic dissection, and mitral regurgitation.¹⁴⁴ Patients with severe valvular disease may require valve replacement surgery, although invasive procedures are problematic given the friability of tissues, easy bleeding, and poor wound healing.

We would like to thank Dr. Mala S. Kaul and Dr. E. William St. Clair, who contributed to the previous version of this chapter in the 13th edition.