Nishant R. Shah, MD

1. What is the leading cause of death in rheumatoid arthritis (RA) and what are the most common cardiac manifestations of RA?

    The leading cause of death in RA is ischemic heart disease. Risk factors attributable to RA include chronic proinflammatory and prothrombotic states, endothelial dysfunction, dyslipidemia, insulin resistance, increased oxidative stress, nonsteroidal antiinflammatory drug (NSAID) use, and corticosteroid use. Other cardiac manifestations of RA include increased risk of congestive heart failure (CHF), pericarditis, and conduction block caused by myocardial rheumatoid nodules.

2. What are the cardiovascular manifestations of systemic lupus erythematosus (SLE)?

    The most common cardiac complication of SLE is pericarditis. Clinically evident myocarditis also occurs in 8% to 25% of patients. Libman-Sacks endocarditis is discussed later. Finally, premature atherosclerosis, due to many of the same independent risk factors noted previously for RA, is now recognized as a major cause of morbidity and mortality.

3. What are the cardiovascular consequences of NSAIDs with predominantly cyclooxygenase-2 (COX-2) inhibition?

    COX-2 inhibitors cause a shift toward thrombosis through reduced endothelial production of prostacyclin (a COX-2–mediated anti-thrombotic process) and relative sparing of platelet production of thromboxane A₂ (a COX-1–mediated pro-thrombotic process). For this reason, concurrent low-dose aspirin is recommended for patients on COX-2 inhibitors. Secondly, COX-2 inhibitors increase sodium and water retention, predisposing patients to edema, CHF exacerbations, and hypertension. Finally, COX-2 inhibitors prevent protective COX-2 upregulation in the setting of myocardial ischemia and infarction, leading to larger infarct size and increased risk of myocardial rupture. Of note, NSAIDs with predominantly COX-1 inhibition are associated with increased risk of gastrointestinal (GI) bleeding. For this reason, concurrent proton-pump inhibitor therapy is recommended for patients on COX-1 inhibitors.

4. What is the major cardiovascular concern associated with tumor necrosis factor (TNF)-α antagonists?

    Results from the Anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial suggest that high-dose TNF-α antagonist therapy actually increases death from any cause and heart failure hospitalization in patients with New York Heart Association (NYHA) class III/IV CHF.

5. What are the clinical manifestations of antiphospholipid antibody syndrome?

    Antiphospholipid antibodies (APLAs) promote intravascular clotting and can be found in primary APLA syndrome or secondary to other conditions, most commonly SLE. Clinical manifestations of APLA syndrome include spontaneous venous and arterial thromboses, strokes and neurologic syndromes, digital and extremity ischemia, livedo reticularis, thrombocytopenia, and recurrent spontaneous abortions. From a cardiac standpoint, acute coronary thromboses and diffuse small-vessel clotting resulting in global myocardial dysfunction have been described. In addition, Libman-Sacks endocarditis, defined by sterile vegetations on the mitral > aortic/tricuspid > pulmonary valves, is thought to arise from organization of thrombi and can cause valvular regurgitation or stenosis requiring surgical correction. Treatment for APLA syndrome is warfarin (goal international normalized ratio [INR] of 2.0-3.0) +/− daily low-dose aspirin, +/− hydroxychloroquine. Drugs associated with drug-induced lupus are given in Table 47-1.

6. Describe the characteristic myocardial lesions of scleroderma and systemic sclerosis and their clinical manifestations.

    Scleroderma of the myocardium manifests as biventricular random patchy fibrosis. Evidence thus far suggests that fibrosis results from recurrent ischemia and reperfusion injury caused by transient recurrent vasospasm of intramural small arteries and/or arterioles (myocardial Raynaud phenomenon). For this reason, calcium channel blocker therapy is appropriate for these patients. Clinically, patients with scleroderma are at increased risk for exercise-induced arrhythmias and biventricular heart failure. Of note, although a septal pseudoinfarct pattern and other conduction abnormalities can be seen on electrocardiography (ECG), a normal ECG is the most common finding.

7. What is the most common cardiac complication of scleroderma and systemic sclerosis?

    Cor pulmonale is the most common complication. Intimal proliferation of the small pulmonary arteries causes pulmonary hypertension and subsequent right-sided heart failure. For this reason, pulmonary function testing (PFT) for diffusion lung capacity for carbon monoxide (DLCO) has become standard in the treatment of scleroderma. Prostacyclin analogues and bosentan have been shown to reduce pulmonary vascular resistance and improve outcomes. Lung transplantation is another treatment option when medical management fails.

8. What are the most common cardiac findings associated with the seronegative spondyloarthropathies?

    Aortic regurgitation (AR) occurs due to aortic root thickening and dilatation, thickening and shortening of the aortic valve cusps, and development of a fibrous “bump.” Mitral regurgitation (MR) is less common, but is due to a similar thickening at the basal portion of the anterior mitral leaflet (or secondary to AR). Complete atrioventricular (AV) nodal or bundle branch block can develop when the fibrosing process extends into the muscular septum. Interestingly, the combination of lone AR and severe conduction system disease in patients not known to have seronegative spondylarthritis is highly correlated with the presence of human leukocyte antigen (HLA)-B27.

9. Name the clinical manifestations of polyarteritis nodosa (PAN), including the most common cardiovascular complications.

    Polyarteritis nodosa is a nongranulomatous, patchy, necrotizing vasculitis of medium-sized muscular arteries. Constitutional symptoms (e.g., fever, malaise, myalgias, arthralgias, and weight loss) are common. Focal tissue ischemia and infarction can cause one of four cutaneous findings (painful subcutaneous nodules, non-blanching livedo reticularis, skin ulceration, or digital ischemia), asymmetric mononeuritis multiplex, hyperreninemic hypertension or renal insufficiency, or mesenteric infarction or aneurysmal rupture. Vasculitis in the distal coronary arteries cause recurrent, small myocardial infarctions (Fig. 47-1) that variably manifest as angina, acute myocardial infarction, congestive heart failure, or arrhythmias. Treatment for PAN is high-dose corticosteroids and cytotoxic therapy (cyclophosphamide, azathioprine, or methotrexate).

10. What are the most common findings in Takayasu arteritis and how should these patients be managed?

    Takayasu arteritis is a granulomatous vasculitis of the aorta and its branches that is most common in young Asian women. Resultant arterial stenosis is much more common than aneurysm formation. Claudication, especially in the upper extremities, is the most common symptom. The most common findings include bruits, hypertension, and upper extremity blood pressure and pulse asymmetry. Aneurysms, when they occur, are most common in the aortic root and can cause significant aortic regurgitation (AR). Angiographic evaluation of the entire aorta and its primary branches, to determine the distribution and severity of vascular lesions, is recommended. When contraindications to angiography exist, magnetic resonance (MR) or computed tomographic (CT) angiography are acceptable alternatives. High-dose corticosteroids and anatomical correction of clinically significant lesions are the treatments of choice. Cyclophosphamide, methotrexate, and anti-TNF agents are reserved for severe disease.

11. What are the most common cardiac manifestations of Kawasaki disease?

    Kawasaki disease is an acute systemic febrile illness most common in infants and young children. Defining symptoms include high-spiking fever, cervical lymphadenopathy (nontender, greater than 1.5 cm in diameter, usually unilateral), erythematous and/or desquamative skin rash, and mucous membrane lesions (oropharyngeal injection, strawberry tongue, bilateral nonexudative conjunctivitis). Typical lab abnormalities include leukocytosis, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and late thrombocytosis. Thrombosis of coronary artery aneurysms (especially those greater than 8 mm) is the most common cause of death. For this reason, serial echocardiography to evaluate coronary artery anatomy and other parameters is crucial. Treatment consists of high-dose aspirin and intravenous immune globulin. A coronary angiogram from a patient with Kawasaki disease is shown in Figure 47-2.

12. What is the most common cardiovascular complications of Marfan syndrome (MFS)?

    MFS is caused by an autosomal dominant fibrillin gene defect. The most common cardiovascular complication is asymptomatic progressive aortic root enlargement beginning at the sinuses of Valsalva. The development of an ascending aortic aneurysm subsequently places patients at high risk for type A aortic dissection, aortic rupture, or aortic regurgitation (AR). Of note, mitral valve prolapse is present in 70% to 90% of MFS patients and progresses to mitral regurgitation in up to 50%.

13. How should MFS be managed from a cardiovascular standpoint?

    Annual imaging with transthoracic or transesophageal echocardiography (or with CT or MR angiography) is required to detect and assess aortic dilatation. When the aortic diameter reaches 5.0 cm, prophylactic aortic root replacement should be considered. Criteria for earlier consideration of surgery include more than 1 cm per year aortic diameter growth, family history of dissection at less than 5 cm, or moderate to severe AR. Finally, MFS patients should be on beta-adrenergic blocking agent (β-blocker) therapy, which has been shown to improve survival.

14. How is Ehlers-Danlos Syndrome (EDS) type IV different from the other types?

    EDS type IV patients have type III collagen defects, resulting in thin, translucent skin absent of the hyperextensibility characterizing other EDS patients. Additionally, EDS type IV patients are at high risk for life-threatening spontaneous arterial rupture, most commonly in the abdominal cavity and the gravid uterus. Bleeding should be managed as conservatively as possible, as these patients’ tissues don’t hold sutures well, and angiography should be avoided due to a high rate of complications.

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