Effects of Systemic Diseases on the Heart and Cardiovascular System

Jay Sengupta and Curtis M. Rimmerman

Many inherited and acquired organ system disorders result in clinically significant changes in the heart and cardiovascular system. These changes often demand specific cardiovascular imaging and therapies in addition to disease-specific treatment. Successfully completing the Cardiovascular Board examination requires an understanding of associated clinical situations. In this chapter, the most commonly tested topics are reviewed, categorized by primary organ system.

INHERITED DISORDERS/GENETIC SYNDROMES

Marfan Syndrome

Marfan syndrome is an autosomal dominant disorder that primarily affects connective tissues as a result of various mutations involving the fibrillin-1 (FBN-1) gene. Mutations in the transforming growth factor (TGF)-beta receptor 2 (TGFBR2) and TGFBR1 genes have been linked to the Marfan phenotype in a minority of cases and a related condition termed Loeys-Dietz syndrome associated with a bifid uvula and cleft palate. The histopathology demonstrates cystic medial necrosis. Mitral valve prolapse and aortic root and aortic annular dilation may be seen, leading to incompetence of the mitral and aortic valves. Aortic disease is the most common cause for morbidity and mortality among Marfan patients and includes aneurysm formation, intramural hematoma, dissection, and rupture. This risk increases significantly with pregnancy.

The 2010 American College of Cardiology/American Heart Association/American Association for Thoracic Surgery (ACC)/(AHA)/(AATS) guidelines for thoracic aortic disease recommend an echocardiogram at the time of diagnosis and in 6 months to determine the aortic root and ascending aortic diameters and their rate of enlargement. Beta-blockers are recommended in all patients with Marfan syndrome and aortic aneurysm to reduce the rate of aortic dilatation. Elective surgical repair is recommended for patients with an external aortic diameter of 5 cm and in patients with aortic diameter <5 cm if there is rapid growth (>0.5 cm/year), family history of aortic dissection at a smaller diameter, or progressive aortic insufficiency In patients with Loeys-Dietz syndrome, aortic dissection has been observed for aortic diameters <5 cm, and therefore surgical repair is recommended at smaller diameters than recommended for Marfan syndrome (>4.2 cm). In all conditions, the height of the individual should also be considered in determining the optimal timing of surgery. Thus, an aorta size of 4.8 cm may be more concerning in an individual who is 60 inches tall in comparison to someone who is 75 inches tall. Algorithms that allow normalization of aorta size for height are available and are useful in these circumstances.

Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome is also an autosomal dominant syndrome that affects the connective tissues and thereby results in similar heart abnormalities. Mitral and tricuspid valve prolapse causing mitral and tricuspid regurgitation, aortic root dilation causing aortic regurgitation, and dissection of the aorta and great vessels comprise the most common cardiovascular complications. When aortic surgery is indicated, patients with Marfan, Loeys-Dietz, or Ehlers-Danlos vascular-type syndromes with a normal aortic valve should undergo valve-sparing aortic root surgery with excision of the sinuses together if feasible or replacement with a valvegraft conduit if the valve is abnormal.

Noonan Syndrome

Noonan syndrome is an autosomal dominant disorder that includes characteristic facies and cognitive impairment in addition to its cardiovascular abnormalities. Heart lesions include pulmonic valve or infundibular stenosis, atrial septal defect, patent ductus arteriosus, tetralogy of Fallot, and hypertrophic cardiomyopathy Vascular abnormalities include peripheral pulmonary arterial stenosis.

Williams Syndrome

Williams syndrome, the result of spontaneous mutations, is characterized by cognitive impairment, an elf-like facies, hypercalcemia, and dental abnormalities. Cardiovascular manifestations include congenital supravalvular aortic stenosis, atrial septal defect, ventricular septal defect, and peripheral pulmonary arterial stenosis.

Osler-Weber-Rendu Syndrome

Also known as hereditary hemorrhagic telangiectasia, Osler-Weber-Rendu syndrome is characterized by mucocutaneous telangiectasias (on the tongue, lips, and fingertips) and arteriovenous malformations (AVMs) in the upper and lower gastrointestinal tracts and pulmonary vasculature. These pulmonary AVMs may result in paradoxical emboli in the presence of venous thrombosis.

NEUROMUSCULAR DISORDERS

Muscular Dystrophy

The three most common variations of muscular dystrophy—Duchenne, Becker, and Emery-Dreifuss—are each X-linked disorders associated with significant cardiac abnormalities. Conduction disturbances are common, especially atrioven-tricular (AV) nodal block and atrial dysrhythmias; atrial paralysis and atrial fibrillation/flutter are particularly common in the Emery-Dreifuss variant. Each muscular dystrophy syndrome may also result in a cardiomyopathy, leading to heart failure. The cardiomyopathy that occurs in Duchenne muscular dystrophy preferentially affects the posterobasal left ventricle, which may exacerbate heart failure by causing posteromedial papillary muscle-mediated mitral regurgitation. Baseline assessment of cardiac function at the time of diagnosis or by the age of 6 years followed by echo or MRI annually or biannually is recommended.

Treatment of the conduction disturbances and cardiomyopathy is supportive; permanent pacing may become indicated. Angiotensin-converting enzyme (ACE) inhibitors may slow the development of LV dysfunction, while the use of ACE inhibitors and beta-blockers may lead to reverse remodeling in patients who have developed dilated cardiomyopathy. Cardiac transplant may be an option in Becker patients with severe dilated cardiomyopathy and no evidence of skeletal muscle disease.

Friedrich Ataxia

Friedrich ataxia is an autosomal recessive neuromuscular disorder, caused by intramitochondrial iron accumulation, resulting in progressive ataxia, areflexia, upper motor neuron injury, and loss of proprioception. From a cardiovascular perspective, it is associated with a hypertrophic cardiomyopathy. Although fatal ventricular dysrhythmias are rare, the cardiomyopathy itself often causes death, especially in cases that progress to dilated cardiomyopathy.

Myotonic Dystrophy

Myotonic dystrophy, also known as Steinert disease, is an autosomal dominant disorder caused by a mutation in the myotonin gene; the resultant phenotype includes myotonia, weakness, frontal balding, cataracts, and gonadal dysfunction in addition to its cardiovascular manifestations. Electrocardiogram changes include pathologic Q waves in the absence of coronary artery disease or myocardial infarction. It also is associated with conduction disturbances, manifested primarily by AV block and intraventricular conduction delay Progression of AV conduction abnormalities is unpredictable and pacing is reasonable in asymptomatic patients with neuromuscular diseases and any degree of AV block.

Kearns-Sayre Syndrome

Kearns-Sayre syndrome is a mitochondrial encephalopathy characterized by ophthalmologic abnormalities. AV block is seen, often requiring pacemaker placement.

Myasthenia Gravis

Myasthenia gravis is an autoimmune process that reduces the number of acetylcholine receptors present at the neuromuscular junction. Affecting more females than males, it presents as progressive weakness and fatigue that worsens with repetitive muscle use and improves with rest. In addition to the autoimmune effect that it has on the neuromuscular endplate, myasthenia gravis can cause a myocarditis that responds to conventional myasthenia gravis treatment modalities.

Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) is an acute, autoimmune-mediated demyelinating disorder of the peripheral nervous system, characterized by ascending motor weakness, paresthesias, and areflexia. The adverse effects that GBS has on the nervous system include autonomic dysfunction involving the cardiovascular system. Hypertension, orthostatic hypotension, resting sinus tachycardia, and potentially fatal dysrhythmias are all potential complications of GBS. Supportive treatment, including plasmapheresis and intravenous immunoglobulin, is the mainstay of care.

ENDOCRINE AND METABOLIC DISORDERS

Acromegaly

Acromegaly results from an excess of circulating growth hormone, usually from overproduction in the pituitary gland. The most common cardiovascular manifestation of this excess is hypertension, with premature atherosclerosis and cardiomegaly also commonly seen. The cardiomegaly is out of proportion to the overall organomegaly and results in congestive heart failure and cardiac dysrhythmias, occasionally resulting in sudden cardiac death.

Treatment consists of destruction of the growth hormone source (i.e., the pituitary gland), either via transsphenoidal surgical resection or external-beam radiation. The associated cardiovascular abnormalities generally can be controlled with conventional therapies; hypertensive patients respond favorably to diuretics and sodium restriction.

Cushing Syndrome

Cushing syndrome is characterized by excess glucocorticoids and androgens, either primarily from adrenal hyperplasia or secondarily from adrenocorticotrophic hormone (ACTH)-producing neoplasms or exogenous administration. Patients with this syndrome are characterized by central obesity with slender extremities and proximal muscle weakness. Associated cardiovascular disorders include hypertension, accelerated atherosclerosis, and dyslipidemia. Cardiac dysrhythmias associated with hypokalemia are seen.

Therapy is directed at the specific cause of the hormonal excess. From a cardiovascular standpoint, efforts should be aimed at controlling hypertension, which is often difficult without first reducing cortisol production and maintaining normal potassium levels.

Hyperaldosteronism/Conn Syndrome

Usually caused by an aldosterone-secreting adenoma, hyperaldosteronism features hypertension, hypokalemia, and metabolic alkalosis. The hypertension can be resistant to multiple medications and severe enough to cause renal insufficiency or stroke. Typical electrocardiogram changes associated with hypokalemia can also occur and manifest as flattened T waves and prominent U waves.

Surgical resection of the adenoma or medical therapy with aldosterone antagonists (e.g., spironolactone, eplerenone) is the treatment of choice, in addition to appropriate potassium replacement.

Adrenal Insufficiency

Adrenal insufficiency can result from (a) primary adrenal cortex failure (Addison disease), (b) hypopituitarism (secondary adrenal insufficiency), (c) selective/isolated hypoaldosteronism (a hyperreninemic state usually caused by a congenital inability to produce aldosterone with preserved glucocorticoid function), or (d) enzymatic deficiency (congenital adrenal hyperplasia). Cardiovascular effects include hypotension with orthostasis and several possible electrocardiogram changes—small/inverted T waves, sinus bradycardia, prolonged QT interval, low-voltage QRS complexes, and first-degree AV block. Treatment consists of replacement with corticosteroids.

Hyperthyroidism

Excess circulating thyroid hormone results in a physiologic state that resembles activation of the sympathetic nervous system. Hyperthyroidism has a peak incidence in the third and fourth decades, and women are four to eight times more likely to be affected.

Cardiac features include palpitations, dyspnea, tachycardia, and systolic hypertension, consistent with the increased chronotropic and inotropic state expected with increased adrenergic tone. Cardiac dysrhythmias and electrocardiogram changes also occur, including atrial fibrillation and other supraventricular tachyarrhythmias, intraventricular conduction delay, and right bundle branch block. Finally, anginal chest pain and congestive heart failure symptoms can occur, even in a structurally normal heart.

Goals of treatment consist of reversal of the hyperthyroid state and resolution of symptoms. The latter is generally accomplished with β-adrenergic-blocking agents; the former can be done medically with targeted antithyroid agents such as methimazole and propylthiouracil, radioactively with ¹³¹I ablation of thyroid tissue, or surgically via thyroidectomy. ACC/AHA/European Society of Cardiology (ESC) guidelines consider thyrotoxicosis a risk factor for throm-boembolism in atrial fibrillation and when associated with one moderate-risk factor recommend anticoagulation until a euthyroid state is restored.

Hypothyroidism

A lack of thyroid hormonal effect will also adversely affect the cardiovascular system. Interstitial myocardial fibrosis can result in gross biventricular dilation. Facial and peripheral edema can progress to brawny, nonpitting myxedema, and myxedematous pericardial effusions can be found in as many as one-third of patients. Electrocardiogram changes may include sinus bradycardia, low-voltage QRS complexes, a prolonged QT interval, and intraventricular conduction delay or right bundle branch block. Hypertension or hypotension may result. Dyslipidemia (hypercholesterolemia and/or hypertriglyc-eridemia) is common.

Thyroid hormone replacement should be instituted at a low initial dose, with small increases in dosage at long intervals, especially in elderly patients or those with known coronary artery disease, as abrupt elevation of thyroid hormone levels can precipitate myocardial ischemia and/or heart failure.

CONNECTIVE TISSUE AND ASSOCIATED VASCULAR DISORDERS

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a well-described autoimmune disorder characterized by antibodies against cellular antigens, resulting in an inflammatory state that is manifested by effects on multiple organ systems. Most commonly, patients with SLE present with arthritis and dermatitis. The most common cardiovascular complication of SLE is pericarditis, with or without pericardial effusion. The effusion, usually exudative, is characterized by an elevated protein concentration, a low/normal glucose concentration, and low complement. Other cardiac abnormalities seen in SLE patients include early coronary artery disease, caused by both progressive atherosclerosis (with chronic corticosteroid use) and coronary arteritis. Myocardial infarction may occur via embolism of noninfectious (Libman-Sacks) endocarditis vegetations, or via SLE-related antiphospholipid antibody (APLA)-mediated thrombosis. The noninfectious endocarditis tends to cause insufficiency of the aortic and mitral valves more commonly, generally sparing the ventricular surface of each valve. Valvular lesions that can be detected by echocardiography are much more common than clinically significant disease. In those patients with clinically significant disease, the tendency is toward valve repair or replacement with bioprosthetic valves rather than mechanical valves, given the propensity of SLE patients to suffer bleeding complications from associated serositis or cerebritis. In patients with the APLA syndrome, mechanical valves are preferred, since anticoagulation is already indicated. Infants born to female patients with SLE (especially those having anti-Ro or anti-La antibodies) may suffer congenital heart block as a result of fibrosis of the conduction system in utero.

SLE-related pericarditis and pericardial effusions should be treated with nonsteroidal anti-inflammatory agents (NSAIDs) initially, with a plan to switch to corticosteroids should more aggressive treatment be necessary. Percutaneous or surgical drainage may be necessary should there be evidence of cardiac tamponade physiology or should maximized medical therapy (corticosteroids and cyclophosphamide) fail to result in resorption of the effusion. Coronary artery disease treatment consists of conventional measures, except in cases of arteritis (which demands an intensive course of corticosteroids) or APLA-mediated thrombosis that requires systemic anticoagulation. In cases of endocarditis, serial echocardiography should be used to monitor for progressive valvular incompetence and indications for surgical valve repair or replacement. Women with SLE who become pregnant should undergo intensive gestational screening; intrauterine dexamethasone has been used successfully to slow progression of congenital heart block.

Some common cardiovascular medications can cause a drug-induced lupus-like syndrome including hydralazine, atenolol, procainamide, statins, captopril, and enalapril. This can occur after months or years of use and is associated with positive antinuclear antibodies (ANA) and antihistone antibodies.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a progressive autoimmune arthritis, resulting in joint destruction, deformation, and immobility. In patients with RA, pericardial disease is the most prominent cardiac complication, ranging in complexity from a chronic asymptomatic effusion to constrictive pericarditis. Early coronary artery disease and myocardial infarction can result from the chronic inflammatory state of RA and the long-term use of corticosteroid therapy. Rarely, secondary amyloidosis will occur, causing an infiltrative cardiomyopathy that may be accompanied by conduction abnormalities.

The mainstay of initial treatment is NSAIDs, followed by more intensive immunosuppression if necessary.

Seronegative Spondyloarthropathies

The seronegative spondyloarthropathies—ankylosing spondylitis, Reiter syndrome, and the inflammatory bowel disease arthritides (ulcerative colitis and Crohn’s disease)—appear to be closely related from a clinical standpoint and are associated with the HLA-B27 antigen. Ankylosing spondylitis results in ankylosis, sacroiliitis, peripheral arthritis, iritis, and aortitis. Reiter syndrome includes asymmetric arthritis, conjunctivitis, and genital ulcers. Aside from the well-described gastrointestinal findings in inflammatory bowel disease, they also feature an asymmetric arthritis and enthesitis. In general, this set of connective tissue disorders also shares a similar cadre of cardiac involvement: a thickened/dilated aortic root, leading to aortic regurgitation, and AV conduction abnormalities.

Polymyositis

Polymyositis is an idiopathic inflammatory myopathy characterized by proximal muscle weakness and elevation of muscle enzyme serum levels. Cardiac involvement consists of a myopericarditis that can either be focal or generalized, at times involving the conduction system and resulting in conduction system abnormalities including heart block. Corticosteroids are generally administered if myocarditis is proven on endomyocardial biopsy.

Scleroderma/CREST Syndrome

Systemic sclerosis, especially when complicated by the CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), can cause pericardial effusions and pericarditis. Patchy myocardial fibrosis may occur as well as conduction system abnormalities at all levels. Pulmonary hypertension can be a prominent feature.

A careful physical examination and echocardiography should be used both to assess for pericardial drainage indications and to monitor pulmonary pressures for significant elevations, possibly requiring the institution of vasodilator therapy.

Takayasu Arteritis

Takayasu arteritis is an idiopathic, granulomatous largevessel vasculitis that generally occurs in young people, with a 10-fold female preponderance and highest incidence found in Japan. Hypertension and aortic regurgitation secondary to aortic annular and aortic root dilation are its most prominent cardiac complications. There is a panarteritis typically affecting the aorta and its major branches. Involvement of the coronary arteries is exceptionally rare.

Clinical classification criteria include age <40 years, claudication especially of the upper extremities, decreased pulses in the brachial artery, blood pressure difference >10 mm Hg between arms, and bruit over the subclavian arteries or the abdominal aorta. Onset is associated with constitutional symptoms such as fever, arthralgias, and weight loss and vessel inflammation can manifest as pain and tenderness, most commonly found over the carotid arteries. Angiography is the gold standard for detecting diseased vessels. Corticosteroids with or without further immunosuppression (cyclo-phosphamide, methotrexate) constitute primary therapy.

The differential diagnosis for vascular symptoms arising from Takayasu’s arteritis includes giant cell/temporal arteritis, Behget disease, fibromuscular dysplasia (FMD), sarcoid vasculopathy, mechanical thoracic outlet syndromes, and infectious or other inflammatory causes for aortitis. Giant cell arteritis shares many clinical, histopathologic, and radiographic findings seen in Takayasu arteritis except that it typically affects individuals older than 50 years of age. It is also associated with new headaches, visual disturbances, and symptoms of polymyalgia rheumatica. Markers of inflammation such as erythrocyte sedimentation rate (ESR) and/or C-reactive protein may be significantly elevated in either condition, and additional findings include constitutional symptoms and jaw and upper extremity claudication. CT or MR angiography can help to distinguish the etiology by demonstrating multisegment stenoses alternating with areas of normal luminal caliber in inflammatory vasculitis versus single stenosis or vascular cutoff at focal sites of functional or mechanical compression.

Fibromuscular Dysplasia

FMD is a noninflammatory, nonatherosclerotic process in which various fibrous lesions in the different layers of the vascular wall lead to arterial stenoses. Any vascular bed can be affected but the most commonly involved vessels are the renal (60% to 75% of cases) and carotid arteries (30% to 60%) followed by mesenteric or brachial arteries and rarely coronary arteries. FMD is more common among females, and the mean age at presentation is 58 years. Renal FMD can manifest as severe or resistant hypertension while involvement of the extracranial vessels can lead to ischemia, spontaneous dissection and occlusion, rupture of aneurysms, or embolic phenomenon. Digital subtraction angiography is the gold standard in diagnosis and shows a classic string-of-beads appearance which differentiates FMD from the inflammatory vasculitides.

Vasculitis Affecting Small to Medium-Sized Vessels

Polyarteritis nodosa (PAN) is a rare necrotizing vasculitis associated with weight loss, myalgias, neuropathy, testicular pain, elevated diastolic blood pressure, renal insufficiency without glomerulonephritis, and false-positive serum hepatitis B testing. The vessels affected by PAN include the coronary arteries. Coronary arteritis and coronary artery aneurysms are seen, which can lead to an acute myocardial infarction. Atherosclerosis is also accelerated in PAN as a result of the associated hypertension, steroid therapy, and renal failure. Corticosteroids are primary therapy.

Churg-Strauss syndrome is an eosinophilic granulomatous inflammation of the respiratory tract, characterized by a necrotizing vasculitis of small and medium-sized vessels. The eosinophilia results in an association with asthma and other atopic diseases. Eosinophilic myocarditis, causing a restrictive cardiomyopathy, pericarditis with or without an associated effusion, and coronary arteritis characterize the cardiac manifestations. Heart failure secondary to the cardiomyopathy is the most common cause of death. Corticosteroids are primary therapy.

Wegener granulomatosis is characterized by systemic granulomatous inflammation of the upper and lower respiratory tract as well as a vasculitis that may result in necrotizing glomerulonephritis. Its cardiac manifestations include pericarditis, myocarditis with left ventricular dysfunction, and an uncommon valvulitis, most often aortic. Serial electrocardiograms and echocardiography to monitor electrophysiologic and ventricular function are warranted, respectively, to guide supportive therapy. Corticosteroids are primary therapy, and cyclophosphamide may be added for progressive disease.

Sarcoidosis

Sarcoidosis is an idiopathic noncaseating granulomatous disorder that predominantly affects the lungs and mediastinal lymph nodes, causing a restrictive pulmonary physiology similar to that of interstitial lung diseases. Sarcoidosis may involve the vascular system, pericardium causing pericarditis, the myocardium causing myocarditis or restrictive cardiomyopathy, and the conduction system causing varying levels of AV and intraventricular block. Ventricular arrhythmias, both benign and malignant, can occur in the presence of myocardial sarcoid infiltration. Endomyocardial biopsy demonstrates granulomatous inflammation but has poor sensitivity. Positron emission tomography in conjunction with CT-imaging can anatomically localize intracardiac and extracardiac inflammation through detection of fludeoxyglucose (18-F) uptake. Cardiac MRI can also be used to improve the sensitivity of diagnosis and typically demonstrates myocardial delayed enhancement with gadolinium. In addition to monitoring for permanent pacing and implantable cardioverter-defibrillator indications, corticosteroids are the mainstay of treatment. In cases of drug-refractory ventricular tachycardia, catheter radiofrequency ablation through endocardial and/or epicardial access may be considered. Patients with advanced heart failure or malignant ventricular arrhythmias may also be considered for cardiac transplantation.

Relapsing Polychondritis

Relapsing polychondritis is an idiopathic, degenerative, inflammatory disease characterized by destruction of cartilage, which results in damage to organs of special sense (outer/inner ear, eyes, nose) in addition to the musculoskeletal system. Relapsing polychondritis can cause aneurysms of the ascending aorta and subsequent aortic regurgitation (because of its effect on the cartilaginous support structures of the mediastinum) as well as vasculitis of vessels ranging in size from the aorta to postcapillary venules. The vasculitis may result in either thrombosis or thrombotic emboli. Corticosteroids are primary therapy.

Behçet Disease

Behçet disease is a chronic inflammatory disease—considered a multisystem vasculitis—characterized by oral aphthous ulcers as well as ulcers of the skin, genitals, and eyes. The vasculitis can result in aneurysms of the arch vessels and the abdominal aorta as well as a proximal aortitis that may cause aortic regurgitation from dilation of the aortic root. Corticosteroids are primary therapy.

HEMATOLOGIC/ONCOLOGIC DISORDERS

Iron Overload

Iron overload may result from primary hemochromatosis, multiple transfusions, intestinal hyperabsorption, and from diseases characterized by bone marrow failure. The most common cardiac complication of iron overload is a restrictive cardiomyopathy secondary to myocardial iron deposition. Pericarditis, AV conduction disorders, and angina, despite normal coronary arteries, also occur. Phlebotomy and chelation therapy with deferoxamine can remove excess iron and a new oral iron chelator, deferiprone, is being tested in patients with sickle cell anemia.

Anemia

Severe anemia can result in left ventricular dysfunction and ultimately congestive heart failure and is associated with a lower quality of life and an impaired survival. Angina may also occur in severe anemia as a consequence of a marked reduction in oxygen transport capacity. For hemolytic anemias related to prosthetic valves, transfusion can increase blood viscosity and reduce valve-related hemolysis. Recent studies of erythropoietin to restore near-normal hemoglobin values in patients with renal failure was associated with increased mortality, hypertension, and thrombosis and in another study did not reduce the composite endpoint of death or a cardiovascular event.

In sickle-cell disease, myocardial infarction may occur with sickling of cells in coronary arteries, leading to coronary artery thrombosis. Acute mitral regurgitation from papillary muscle involvement can complicate myocardial infarctions in sickle-cell disease. Pulmonary infarction may also occur, from either pulmonary arterial thrombosis or embolization of venous thrombi.

Polycythemia

In addition to polycythemia vera, other polycythemic states may result in adverse cardiovascular effects. Like polycythemia vera, thrombocytosis, leukocytosis, plasma cell neoplasms, monoclonal gammopathies such as multiple myeloma, and cryoglobulinemia each may cause a hyperviscosity syndrome, leading to vascular thrombosis. Coronary arterial thrombosis may result in myocardial infarction, deep venous thrombosis can lead to pulmonary embolism, and peripheral arterial thrombosis may cause skeletal muscle or organ-specific infarction.

Therapy is focused on reducing the polycythemic load with treatment specific to the involved cell line. Polycythemia vera and thrombocytosis may respond to hydroxyurea. Leukocytoses and plasma cell neoplasms should be treated with appropriate chemotherapeutics, and, in the case of paraproteinemias, plasmapheresis is an important adjunctive therapy.

Neoplastic Disease

Tumors originating in the heart and those that commonly metastasize to the myocardium are discussed in the Cardiac Tumors chapter. Pericardial disease may take the form of metastatic infiltration causing a constrictive physiology or it may be effusive, resulting in possible cardiac tamponade. Noninfectious, nonmetastatic, thrombotic endocarditis, also known as marantic endocarditis, may occur. Marantic endocarditis generally does not destroy valve architecture or disrupt valvular function but does predispose to peripheral embolism. Myocardial ischemia is a potential complication of thrombotic emboli or extrinsic compression of epicardial coronary arteries. Dysrhythmias are common with metastases to the myocardium. The superior vena cava (SVC) syndrome, caused by extrinsic compression of the SVC by tumor or enlarged lymph nodes resulting in venous stasis in the head, arms, and upper torso, may also complicate malignancies.

Effusive pericardial disease is treated with percutaneous or surgical drainage, whereas infiltrative pericardial disease requires surgical pericardial stripping. The presence of marantic endocarditis requires no specific therapy, though treating ischemic syndromes that may result or occur concomitantly requires anticoagulation that may precipitate further embolic phenomena. The SVC syndrome requires urgent combination therapy with external-beam radiation and chemotherapy, and endovascular stenting has become a common adjunctive treatment.

External-Beam Radiation Therapy

Patients who receive external-beam radiation (XRT) for chest wall or mediastinal tumors often suffer heart-specific side effects. Pericardial disease may range from an effusion to calcific constrictive pericarditis. Coronary arteries may undergo accelerated atherosclerosis or narrowing, a form of radiation fibrosis. Heart valves may also be damaged, resulting in valvulitis that can cause either stenosis or regurgitation. XRT may also cause a cardiomyopathy from direct myocardial damage, though this can be difficult to distinguish from a cardiomyopathy caused by simultaneously used chemotherapeutic agents.

Pericardial disease is treated with drainage or pericardial stripping. Coronary artery disease should be managed with conventional therapies, and valvulitis requires serial echocardiography to determine timing of surgical repair or replacement. XRT-related cardiomyopathy is managed by usual congestive heart failure therapies.

Chemotherapy

Anthracycline chemotherapeutics and mitoxantrone (a chemically similar antineoplastic medication) are known to cause a well-described dilated cardiomyopathy that is related to cumulative dose. The cardiomyopathy should be treated with conventional congestive heart failure therapy. These drugs may also cause an acute toxicity, characterized by electrocardiogram changes that include a prolonged QT interval and nonspecific ST-segment and T-wave changes. Other chemotherapeutics are also identified as cardiotoxins. Ischemic coronary syndromes may be precipitated by 5-fluorouracil in patients with preexisting coronary artery disease. Treatment consists of usual coronary artery disease management. Cyclophosphamide and ifosfamide have been shown to cause a cardiomyopathy similar to that observed with the anthracyclines and should be managed similarly. Small-molecule kinase inhibitors and antibody-based therapies targeting signaling pathways in cancer such as sunitinib, imatinib, trastuzumab, and sorafenib have been associated with drug-induced cardiac injury in a subset of treated individuals.

RENAL FAILURE

Although congestive heart failure may lead to renal insufficiency, the reverse may also occur. Uremic cardiomyopathy may result from volume and pressure overload related to insufficient fluid clearance, and circulating uremic toxins have a negative inotropic effect. As with most secondary cardiomyopathies, treatment consists of conventional congestive heart failure management measures.

Accelerated atherosclerosis can result from the hyper-lipidemia that constitutes a component of the nephrotic syndrome, which should be treated with aggressive medical therapy. Hypertension can also occur as a result of renal failure, especially in cases caused by arterionephrosclerosis, glomerulopathies, or transplant-associated renal failure. Treatment consists of antihypertensive medications and early hemodialysis as the renal failure progresses.

Calcification of the heart’s valvular apparatus, coronary arteries, conduction system, and pericardium may develop as the calcium phosphorus product increases with worsening renal failure. Diet modification and phosphate-binding agents are the treatments of choice.

Furthermore, pericardial disease in renal failure ranges from constriction to uremic pericarditis with effusion. Percutaneous or surgical drainage may be required. Effective hemodialysis can reduce the likelihood of developing further effusions.

Because of the rapid changes in electrolytes and pH that accompany dialysis and the high prevalence of underlying heart disease among patients with renal failure, dysrhythmias are common, requiring supportive care and close monitoring of electrolytes both pre- and postdialysis.

HIV

Among the protean clinical manifestations of HIV, the heart is not spared. Left ventricular dysfunction results as HIV infection progresses to individual cardiac myocytes, causing focal myocarditis. This cardiomyopathy is more common as the CD4+ cell count decreases and tends to occur more frequently in infected children. Treatment consists of usual measures for dilated cardiomyopathy.

As HIV progresses, the release of cytokines to fight opportunistic infections and to signal maximal activation of the immune system compromises endothelial integrity at the capillary level. This results in pleural, peritoneal, and pericardial effusions. The presence of a pericardial effusion markedly increases predicted mortality. Screening echocar-diography is a reasonable consideration in the later stages of HIV, and percutaneous or surgical drainage may become necessary in the presence of hemodynamic compromise or to examine fluid for treatable opportunistic etiologies (e.g., tuberculosis, malignancy).

The chronic inflammatory state present in HIV and lipid-raising tendency of protease inhibitors may result in accelerated atherosclerosis of the coronary arteries. Patients on antiretrovi-ral therapy should receive aggressive lipid-lowering therapy, and a high degree of suspicion should exist in even young HIV+ patients presenting with possible anginal syndromes.

A heart-specific opportunistic infection occurring in the setting of HIV is Salmonella endocarditis, as the transient bacteremia that may occur after ingestion of affected food will not be effectively cleared. Fungal endocarditis is also included on the list of HIV-associated opportunistic infections. Treatment consists of broad-spectrum antibiotic therapy pending isolation of a specific pathogen.

Finally, HIV-associated malignancies may involve the heart as well, most commonly metastatic Kaposi sarcoma and lymphomas, which may be heralded by pericardial effusions. Treatment is specifically directed at the identified malignancy.

Antiretroviral therapy is implicated in increasing metabolic and cardiovascular risk. All HIV-infected individuals should be evaluated regularly for lipid abnormalities, hyperglycemia, hypertension, and obesity as part of risk stratification for coronary artery disease. Selection of retroviral medications to minimize metabolic risk without compromising suppression of viral replication must be considered.

CONCLUSION

Given the spectrum of noncardiac disease that may significantly affect the heart and cardiovascular system, a working knowledge of these interactions is essential for treatment of patients with cardiovascular disease and for success on the Cardiovascular Medicine Board Examination. Effective care for patients with systemic disease demands cooperation with internists as well as medical and surgical subspecialists.

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