The SAPPHIRE trial is the only published randomized trial that has com- pared carotid endar terectomy with carotid artery stenting. Patients had at least one high-risk surgical featur e and were included with symptomatic carotid stenosis of >50% or asymptomatic carotid steno sis of >80%. While the primary end point was complex, the carotid-stent arm of the trial ha d signi \201 cantly less composite stroke, MI, and death within 30 days. An ongoing trial of carotid revascularization endarterectomy vs. stent trial (CREST) is rev iewing both treatment strategies in 1400 patients with a goal of 4-year follow-up. CHAPTER 3 Peripheral vascular disease 156 Table 3.5 Causes of stroke Intracardiac thrombus Intracardiac mass lesions Valvular heart disease Infectious endocarditis Paradoxic emboli Large vessel occlusive disease Small-vessel disease (hypertension, DM, arteritis) Carotid atherosclerosis Polycythemia vera Thrombocytosis Antiphospholipid antibody syndrome Cryoglobulinemia Air and fat emboli Cortical vein thrombosis RENOVASCULAR DISEASE 157 Renovascular disease Obstructive renovascular disease can be caused by atherosclerosis or \201 bromuscular dysplasia (FMD). Renal FMD tends to occur in younger patients. There is a female preponderance. FMD typically involves the secondary or distal branches. Renal artery revascularization wit h surgery or percutaneous angioplasty techniques can be curative of hypertension. While the true prevalence of atherosclerotic renal artery disease is not known, in patients identi \201 ed as having atherosclerosis in other vascular beds the prevalence is between 10% and 30%. The true natural history of renal atherosclerotic disease, outcomes after rev ascularization, and appro- priate populations for intervention still require clari \201 ca tion. Clinical signs include known atherosclerosis in alternate vascular beds, onset of hypertens ion (HTN) prior to age 30 (FMD) or after age 55, wors- ening of previously controlled HTN, malignant or resistant hypertension, abdominal or \202 ank bruit, discrepancy in renal si ze, unexplained azotemia or renal function worsened by ACE inhibitors or angiotensin II rec eptor blockers (ARBs), and recurrent heart failure or \202 ash pulmonary edema in a hyper tensive patient with preserved LV function. Diagnostic testing MRA, CTA, and duplex Doppler ultrasonography can be used in the diag- no sis of renal artery stenosis (RAS) (see Fig. 3.11). Captopril renal scintig- raphy, selecti ve renal vein renin measurements, and plasma renin activity are not useful screening tests for RAS. Both MRA and CTA have lower diagnostic accuracy, with sensitivity in 20% \200\22330% range, for lesions caused by FMD. This is likely secondary to their anatomic location. Magnetic resonance angiography Multiple series have shown the high diagnostic accuracy of M RA and increasingly this is becoming the \201 rst-line diagnostic test. Because of links to administration of gadolinium in patients with moderate to severe renal disease to nephro genic systemic \201 brosis, MRA is not recommended in patients with a glomerular \201 l tration rate (GFR) <30. CT angiography Spiral CT with administration of contrast allows for highly accurate non- in vasive imaging of renal arteries. Sensitivity and speci \201 city are roughly in the high 70% and mid 90% range, respectively. Duplex Doppler ultrasonography This allows for both functional and anatomic assessment of R AS. Direct visualization is combined with Doppler measurements for hemodynamic assessment. The sensitivity and speci \201 city are 85% and 92%, respectively. CHAPTER 3 Peripheral vascular disease 158 Clinical Clues to the Diagnosis of Renal Artery Stenosis 1. Onset of hypertension before the age of 30 years of severe hypertension after the age of 55.* (Class I; LOE B) 2. Accelerated, resistant, or malignant ypertension.* (Class I; LOE C) 3. Development of new azotemia or worsening renal function after administration of an AC E inhibitor or ARB agent. (Class I; LOE B) 4. Unexplained atrophic kidney or size discrepan cy between kidneys of greater than 1.5 cm. \200 (Class I; LOE B) 5. Sudden, unexplained pu lmonary edema. (Class I; LOE B) 6. Unexplained renal dysfunction, including individuals sta rting renal replacement therapy. (Class IIa; LOE B) 7. Multi-vessel coronary artery disease . (Class IIb; LOE B) 8. Unexplained congestive heart failure. (Class IIb; LOE C) 9. Refract ory angina. (Class IIb; LOE C) Diagnostic Studies Invasive Imaging Abdominal aortography to assess the renal arteries during coronary and per ipherals angiography Noninvasive Imaging \200 Duplex ultrasound \200 Gadolinium enhanced MRA \200 CT angio graphy Negative noninvasive test result but high clinical index of suspicion Evidence of RAS Evidence of RAS Renal angiography (and hemodynamics) Evidence of RAS See Treatment See Treatment See Treatment Figure 3.11 Clinical clues to the diagnosis of renal artery stenosis (RAS). * For de \201 nition of hypertension, please see Chobanian AV, Bakris GL, Black HR, et al. (2003). The Se venth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Trea tment of High Blood Pressure: the JNC-7 report. JAMA 289:2560 \200\2232572. \200 For exam ple, atrophic kidney due to chronic pyelonephritis is not an indication for RAS evaluation. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocking agent; CT, computed tomography; LOE, level of evidence; MRA, magnetic resonance angiography. Reprinted with pe rmission from the ACC/AHA Practice Guidelines. Hirsch et al. (2006). Circulation 113:e463 \200\223e465. RENOVASCULAR DISEASE 159 Revascularization Angiographic lesions >75% in one or both renal arteries suggest reno- vas cular disease. It is important to remember that such \201 ndings may be present in patien ts with or without hypertension who have other vascular disease. The clinical history is particularly important in helping to select patients who are approp riate for percutaneous revascularization (Fig. 3.12). By repeat duplex sonography, while RA S lesion severity may increase over time in most patients, the progression to renal failure is uncommon. The decision to revascularize an RAS is based on the assumption that clinical bene \201 t will be derived from the intervention. The evaluation of resistive index (1-end diastolic v elocity divided by peak systolic velocity) prior to angioplasty may predict which patients will have a successful revascularization procedure. A higher resistive index, >8, may indic ate irreversible intrarenal vascular arteriosclerosis. The procedure is performed from a femoral approach and technical success varies based on the location of the lesion. In general, results are much better with FMD, with <15% procedural failure and infrequent r estenosis rate. In atherosclerotic disease, the failure rate approximates 20% \200\22330% a nd the restenosis rate is between 8% and 30%. The ef \201 cacy of angioplasty improves by insertion of a stent. While clinical trials are limited, anecdotal experience suggests that drug- eluting stents may signi \201 cantly reduce restenosis rates. The current ACC/ AHA guidelines recommend s tenting for ostial atherosclerotic lesions in patients who meet clinical criteria. However, for FMD the guidelines rec- ommend balloon angioplasty with bailout stent placement, if ne cessary. The procedural complication rate is between 5% and 15%. Complications include puncture site hematoma, renal artery dissection, renal artery thrombosis or perforation, and acute renal failure from atheroembolism or contrast-induced nephropathy. Distal embolic protection dev ices have been advocated to help to reduce the complications of atheroembolism. Surgical revascularization is recommended by ACC/AHA guidelines for patients who have indic ations for revasculrization, have small renal arteries, or require aortic reconstruction ne ar the renal arteries for other indications. While surgery is generally more effective in t reating athero- sclerotic renovascular disease, the mortality rate may be as high as 5% \200\2238% in older patients. 1 6 0 RAS with: \200 Accelerated, resistant, or malignant hypertension \200 Hypertension with unilateral small kidney \200 Hypertension with medication intolerance (Class IIa; LOE B) C H A P T E R Hemodynamically significant RAS with recurrent, unexplained CHF or sudden, unexplained pulm onary edema (Class I; LOE B) RAS and CRI with bilateral RAS or RAS to solitary functioning kidney (Class IIa; LOE B) RAS and CRI with unilateral RAS (2 kidneys present) (Class IIb; LOE C) Asymptomatic unilateral hemodynamically significant RAS in a viable* kidney (Class IIb; LOE C) Asymptomatic Bilateral or solitary viable* kidney with a hemodynamically significant RAS (C lass IIb; LOE C) RAS and unstable angina (Class IIa; LOE B) 3 P e r i p h e r a l v a s c u l a r Renal artery surgery \200 Renal angioplasty/stent \200 Atherosclerotic RAS Fibromuscular dysplasia RAS d i s e a s e PTA (with \200\234bailout \200\235 stent use) is indicated for patients meeting criteria f or intervention (Class I; LOE B) Stent use is indicated in patients who meet criteria for intervention (Class I; LOE B) Figure 3.12 Indications for renal revascularization. * \200\234Viable \200\235 means kidne y linear length >7 cm. \200 It is recognized that renal artery surgery has proven ef \201 cacy in alleviating renal artery stenosis (RAS) due to atherosclerosis and \201 brom uscular dysplasia. Currently, however, its role is often reserved for individuals in whom l ess invasive percutaneous RAS interventions are not feasible. CHF, congestive heart failure ; CRI, chronic renal insuf \201 ciency; LOE, level of evidence; PTA, percutaneous translum inal angioplasty. Reprinted with permission from the ACC/AHA Practice Guidelines. Hirsch et al. (2006). Circulation 113:e463 \200\223e465. AORTIC DISEASE 161 Aortic disease Aortic atheroembolism This represents an important cause of micro- and macro emboli in both the cerebral and systemic circulation. Cerebral embolism suggests the source of embolism is intracardiac or within the ascending/transverse aorta, whereas peripheral e mbolism is most commonly caused by abdom- inal aortic aneursym or diffuse atherosclerotic d isease. Clinical features include livedo reticularis, blue toes, palpable pulses, hypertension, ren al insuf \201 ciency, elevated erythrocyte sedimentation rate, and eosinophilia. Thoracic aortic atherosclerotic plaque is most accurately assessed by TEE. Plaque thickness >4 mm or mobile plaque of any size is associated with an increased risk of embolization. Treatment includes the use of antiplatelet medications and statin therapy, as well as ident i \201 cation and, if possible, surgical resection of the source of embolism. Thoracic aortic aneurysm (TAA) TAAs are most commonly caused by atherosclerosis. They can a lso occur with systemic hypertension, Marfan syndrome, bicuspid aortic valve, giant cell ar teritis, Takayasu disease, infections (syphilis), and trauma. Most TAAs are asymptomatic and discovered incidentally and can be diagnosed noninvasively with CT, MRI, and TEE. Surgical resection should be considered if symptoms attributable to the aneursym are presen t, if the aneursym is rapidly enlarging, if pseu- doaneurysm is present, if there is a post -traumatic aneursym, and if the aneursym size is >6 cm in low-risk patients and 4.5 cm or g reater in Marfan patients. Abdominal aortic aneursym (AAA) In high-risk patients, screening tests are recommended beca use the phys- ical exam lacks sensitivity. A single screening abdominal ultrasound over the age of 65 can diagnose the majority of AAAs. The United States Prevention Services Task fo rce recommends a one-time screening ultra- sound in men ages 65 \200\22375 who have ever sm oked. In siblings and \201 rst-degree relatives of patients with AAA, screening typically begins at age 50. \200 Elective surgical repair is indicated when the aneurysm diameter is between 5.5 and 6.0 cm in good-risk patients (Fig. 3.13). Surgery is also recommended for AAAs that are symptomati c, traumatic, or infectious in origin or are expanding >0.5 cm/year. In high-risk patients, surgical therapy is individualized. In these patients, endovascular approach with a stent- anchored Dacron prosthetic graft provides an alternate therapeutic option (Fig. 3.14). All patients with endovascular repair will need continued lifelong tomo- graphic imaging. CHAPTER 3 Peripheral vascular disease 162 Abdominal Aortic Aneurysm Pararenal, suprarenal, or type IV thoracoabdominal Infrarenal Symptomatic intact Symptomatic intact Ruptured Asymptomatic Asymptomatic Greater than or equal to 5.5 growth growth spurt Smaller than 4 cm Greater than or equal to 5.5 to 6.0 cm or growth spurt Smaller than 4 cm 4 to 5.4 cm 4 to 5.4 cm Annual contrast CT or MR scan Biennial ultrasound scan Contrast CT or MR scan every 6 to 12 months 4 to 5.4 cm Ultrasound scan every 6 to 12 months 4 to 5.4 cm Medical evaluation Contrast CT or MR scan Medical evaluation Low or average risk High risk Low or average risk High risk Continued CT or MR surveillance Elective open repair Endograft repair if aortic anatomy appropriate Continued CT or MR surveillance Elective open repair Symptoms or growth spurt Symptoms or growth spurt High risk Low or average risk Urgent open repair Urgent open repair Figure 3.13 Management of abdominal aortic aneuryms. CT, computed tomography; MR, magnetic resonance imaging. Reprinted with permission from the ACC/AHA Practice Guidelines. Hirsch e t al. (2006). Circulation 113:e463 \200\223e465. AORTIC DISEASE 163 (a) (b) (c) (d) Figure 3.14 Diagram of deployment of an aortic stent graft. a) The catheter placement and p roximal stabilization are achieved via right femoral access. b) The body and right limb of the stent graft are positioned and deployed. c) The cannula for deployment of the left limb of the graft is placed via left femoral access. d) The left limb of the graft is deployed, completing the endovascular repair of the aortic aneurysm with left iliac involvement. Thi s \201 gure was published in Libby et al., Braunwald \200\231s Heart Disease, 8th ed., p. 1462. Copyright Elsevier 2007. Aortic dissection The most common predisposing factors for dissection include advanced age, male gender, hypertension, Marfan syndrome, and bicuspid/unicuspid aortic valve. Iatrogeni c aortic dissection can occur with surgical and inva- sive angiographic procedures (Fig. 3. 15). Clinical features include severe pain in the anterior chest, back, or abdo- men; hypertensi on; aortic diastolic murmur; pulse de \201 cits or blood pres- sure differential; and neur ological changes. Syncope can occur when there is extension of the dissection into the pericardial sac with r esulting cardiac tamponade. Congestive heart failure occurs from severe aortic regurgitatio n. CXR may reveal widened medi- astinum, discrepancy in the sizes of ascending vs. descendi ng aorta, and deviation of the trachea to the right. De \201 nitive diagnosis can be made with prompt imaging, including echocardiography, CT, MRI, and aortography. In a patient with acute sus- pected aortic dissection, test selection should depend on the most readily available test at your institution. Type I and II dissections should have emergent surgery. Medical ther- apy includes IV antih ypertensive medications to decrease mean arterial pressure. Penetrating aortic ulcer This occurs when atherosclerotic plaque undergoes ulceration and p en- etrates the internal elastic lamina. It can result in several consequences: formation o f an intramural hematoma, formation of saccular aneursym, formation of pseudoaneurysm, or t ransmural rupture. The clinical features are similar to those of aortic dissection; however, pulse de \201 ci ts, neurological signs, and acute cardiac disease are not seen with penetrating aortic ulce r. CHAPTER 3 Peripheral vascular disease 164 Type III Type II Type I Figure 3.15 Commonly used classi \201 cation systems for aortic dissection. This \201 gu re was published in Libby et al., Braunwald \200\231s Heart Disease, 8th ed., p. 1470. Copy right Elsevier 2007. The diagnosis can be made with CT, MRI, TEE, or aortography. The treatment is nonoperative only if a intramural hematoma is present, whereas surgical treatment is recommended for pat ients with ascending aorta involvement, saccular aneursym, or pseudoaneursym, or for patien ts with intramural hematoma with persisting symptoms, increasing aortic diameter, or poorly controlled hypertension. Incomplete aortic rupture This results from deceleration injuries and typically involves th e thoracic aorta at the isthmus. While this is seen most frequently in patients who have been in a motor vehicle accident, i t should be considered in any patient where there is evidence of chest wall trauma, decreas ed or absent leg pulses, left-sided hemothorax, or widening of the superior mediastinum on CXR. The diagnosis can be con \201 rmed by TEE, CT, MRI, or angiography. Treatment is emergent surgical repair. AORTIC DISEASE 165 <3 cm Type A Endovascular treatment of choice <3 cm Type B Currently, endovascular treatment is more often used but insufficient evidence for r ecommendation 3 \200\2235 cm 3 \200\2235 cm 3 \200\22310 cm Type C Currently surgical treatment is more often used but insufficient evidence for recomm endation 5 \200\22310 cm 5 \200\22310 cm Type D Surgical treatment of choice Figure 3.16 Summary of preferred options in interventional management of iliac lesions. Rep rinted with permission from Dormandy JA, Rutherford RB. TASC Working Group (2000). Endovasc ular procedures for intermittent claudication. J Vasc Surg 31(1) Supplement 1:S97 \200\223S 113. CHAPTER 3 Peripheral vascular disease 166 Noninvasive and invasive vascular diagnostic tools Noninvasive and invasive vascular diagnostic tools: bene \201 ts and limitations Diagnostic tool* Bene \201 ts Limitations May not be accurate when systolic blood pressure cannot be abolished by in \202 ation of a n air- \201 lled blood pressure cuff (non-compressible pedal arteries), as occurs in a sma ll fraction of diabetic or very elderly individuals Ankle \200\223brachial indices (ABIs) A quick and cost-effective way to establish or refute the lower extremity PAD diagnosis (se e text) Requires small cuffs and careful technique to preserve accuracy Toe \200\223brachial indices A quick and cost-effective way to establish or refute the lower extremity PAD diagnosis (se e text) Can measure digital perfusion when small-vessel arterial occlusive disease is prese nt Useful in individuals with noncompressible posterior tibial or dorsalis pedis arteries May not be accurate when systolic blood pressure cannot be measured by in \202 ation of an air- \201 lled blood pressure cuff owing to noncompressible pedal arteries, as occurs in a small fraction of diabetic or very elderly individuals Useful to establish or refute the PAD diagnosis (see text) Useful to provide anatomic local ization of lower extremity PAD when data are required to create a therapeutic plan Can prov ide data to predict limb survival, wound healing, and patient survival Useful to monitor th e ef \201 cacy of therapeutic interventions Segmental pressure examination Usefulness maintained in patients with noncompressible vessels (ABI value >1.3) Qualitative , not quantitative, measure of perfusion May not be accurate in more distal segments Less a ccurate than other non- invasive tests in providing arterial anatomic localization of PAD M ay be abnormal in patients with low cardiac stroke volume Pulse volume recording Useful to establish diagnosis of PAD in vascular laboratories or of \201 ce practice Helpf ul in predicting outcome in CLI and risk of amputation Can be used to monitor limb perfusio n after revascularization procedures NONINVASIVE AND INVASIVE VASCULAR DIAGNOSTIC TOOLS 167 Diagnostic tool* Bene \201 ts Limitations \200\234Pulse normalization \200\235 downstream from stenoses can diminish test sensitivit y Test speci \201 city greater for patent super \201 cial femoral arteries than for aorto iliac occlusive disease Does not provide visualization of arterial anatomy Limited accuracy in tortuous, overlapping, or densely calci \201 ed arterial segments, and insensitive for iliac arteries (in context of obesity, bowel gas, and vessel tortuosity) Useful to assess lower extremity PAD anatomy, severity, and progression Can provide localiz ing information in patients with poorly compressible arteries Can provide quantitative data after successful lower extremity revascularization Continuous- wave Doppler ultrasound Useful tool to provide graft surveillance after femoral- popliteal or femoral tibial or ped al surgical bypass with venous (but not prosthetic) conduit Accuracy is diminished in proxi mal aortoiliac arterial segments in some individuals (e.g., due to obesity or presence of b owel gas) Dense arterial calci \201 cation can limit diagnostic accuracy Sensitivity is di minished for detection of stenoses downstream from a proximal stenosis Duplex ultrasound Can establish the lower extremity PAD diagnosis, establish anatomic localization, and de \201 ne severity of focal lower extremity arterial stenoses Can be useful to select candida tes for endovascular or surgical revascularization Diminished predictive value in surveillance of prosthetic bypass grafts Provides qualitativ e (rather than quantitative) exercise diagnostic results Lower workload may not elicit symp toms in all individuals with claudication Useful to diagnose lower extremity PAD when resting ABI values are normal Can be performed without a treadmill, with increased convenience and low cost Toe-tip exercise testing, with pre-exercise and post- exercise ABIs Requires use of a motorized treadmill, with or without continuous ECG monitoring, as well a s staff familiar with exercise testing protocols Helps differentiate claudication from pseudoclaudication in individuals with exertional leg symptoms Useful to diagnose lower extremity PAD when resting ABI values are normal Treadmill exercise testing, with and without pre- exercise and postexercise ABIs CHAPTER 3 Peripheral vascular disease 168 Diagnostic tool* Bene \201 ts Limitations Objectively documents magnitude of symptom limitation in patients with claudication, especi ally when used with a standardized treadmill protocol Demonstrates safety of exercise and p rovides data to individualize exercise prescriptions in individuals with claudication befor e initiation of a formal program of therapeutic exercise training Useful to measure objecti ve functional response to claudication therapeutic interventions Tends to overestimate degree of stenosis May be inaccurate in arteries treated with metal stents Cannot be used in patients with contraindications to the magnetic resonance techniq ue (e.g., pacemakers, de \201 brillators, intracranial metallic stents, clips, coils, and other devices) Useful to assess PAD anatomy and presence of signi \201 cant stenoses Useful to select pat ients who are candidates for endovascular or surgical revascularization Magnetic resonance angiography (MRA) Single-detector computed tomography lacks accuracy for detection of stenosis Spatial resolu tion lower than that of digital subtraction angiography Venous opaci \201 cation can obscu re arterial \201 lling Asymmetrical opaci \201 cation of the legs may obscure arterial p hase in some vessels Accuracy and effectiveness are not as well determined as with MRA Trea tment plans based on CTA have not been compared with those of catheter angiography Requires iodinated contrast and ionizing radiation (although radiation exposure is less than with c atheter angiography) Useful to assess PAD anatomy and presence of signi \201 cant stenoses Useful to select pat ients who are candidates for endovascular or surgical revascularization Helpful to provide associated soft tissue diagnostic information that may be associated with PAD presentation (e.g., aneurysms, popliteal entrapment, and cystic adventitial disease) Patients with contr aindications to MRA (e.g., pacemakers or de \201 brillators) may be safely imaged Computed tomographic angiography (CTA) NONINVASIVE AND INVASIVE VASCULAR DIAGNOSTIC TOOLS 169 Diagnostic tool* Bene \201 ts Limitations Because CTA requires administration of iodinated contrast, use is limited in individuals wi th established renal dysfunction Metal clips, stents, and metallic prostheses do not cause signi \201 cant CTA artifacts Sc an times are signi \201 cantly faster than for MRA Invasive evaluation is associated with risk of bleeding, infection, vascular access complic ations (e.g., dissection or hematoma), athero- embolization, contrast allergy, and contrast nephropathy May provide limited visualization of tibial-pedal vessels in patients with CLI and poor in \202 ow to the leg Below-knee vessels may be dif \201 cult to identify by di gital subtraction angiography Multiple projections may be necessary to visualize eccentric lesions Contrast angiography De \201 nitive method for anatomic evaluation of PAD when revascularization is planned Tools are listed in order from least invasive to most invasive and from least to most costl y. CLI, critical limb ischemia; PAD, peripheral arterial disease. Reprinted with permission from the ACC/AHA Practice Guidelines. Hirsch et al. (2006). Circulation 113:e463 \200\223e 465. CHAPTER 3 Peripheral vascular disease 170 Further reading Aboyans V, Criqui MH, Denenberg JO, et al. (2006). Risk factors for progression of peripher al arte- rial disease in large and small vessels. Circulation 113:2623 \200\2232629. Ailawadi, G, Eliason JL, Upchurch GR Jr (2003). Current concepts in the pathogenesis of abd ominal aortic aneursym. J Vasc Surg 38:584. Barani J, Nilsson JA, Mattiasson I, et al (2005). In \202 ammatory mediators are associate d with 1-year mortality in critical limb ischemia. J Vasc Surg 42:75 \200\22380. Braunwald E, et al. (2004). Braunwald \200\231s Heart Disease: A Textbook of Cardiovascular Medicine. St. Louis: WB Saunders. Creager MA, Dzau VJ, Loscalzo J, ed. (2006). Vascular Medicine: A Companion to Braunwald \200\231s Heart Disease, Philadelphia: Elsevier; pp. 934 \200\223960. Criqui, MH (2001). Peripheral arterial disease \200\224epidemiological aspects. Vasc Med; 6 :3 \200\2237. Criqui MH, Langer, RD, Franek, A, et al. (1992). Mortality over a period of 1 0 years in patients with peripheral arterial disease. N Engl J Med 326:381. Criqui MH, Ninomiya J: The epidemiology of peripheral arterial disease. In: MA Creager, Dza u VJ, Loscalzo J, ed. Vascular Medicine: A Companion to Braunwald \200\231s Heart Disease, Philadelphia: Elsevier; 2006:223 \200\223238. Criqui MH, Vargas V, Denenberg JO, et al. (2005) Ethnicity and peripheral arterial disease: The San Diego Population Study. Circulation 112:2703 \200\2232707. Diehm C, Schuster A, Allenberg JR, et al. (2004). High prevalence of peripheral arterial di sease and co-morbidity in 6880 primary care patients: Cross-sectional study. Atherosclerosi s 172:95 \200\223105. Hiatt WR, Brass EP (2006). Pathophysiology of intermittent claudicati on. In Creager MA, Dzau VJ, Loscalzo J (Eds.), Vascular Medicine: A Companion to Braunwald \200\231s Heart Disease. Philadelphia: Elsevier; pp. 239 \200\223247. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. (2001). Peripheral arterial disease detectio n, aware- ness, and treatment in primary care. JAMA 286:1317. Hirsch AT, Haskal ZJ, Hertzer NR, et al. (2006). ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdo minal aortic): Executive summary a collaborative report from the American Association for V ascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and In terventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology , and the ACC/ AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelin es for the Management of Patients With Peripheral Arterial Disease) endorsed by the America n Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blo od Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vasc ular Disease Foundation. J Am Coll Cardiol 47:1239 \200\2231312. Jude EB, Oyiba SO, Chalmers N, Boulton AJ (2001). Peripheral arterial disease in diabetic a nd nondiabetic patients: a comparison of severity and outcome. Diabetes Care 24:1433. Libby P, et al. (2008). Braunwald \200\231s Heart Disease: A Textbook of Cardiovascular Med icine. Philadelphia: Elsevier. Lu JT, Creager MA (2004). The relationship of cigarette smoking to peripheral arterial dise ase. Rev Cardiovasc Med 5:189 \200\223193. Marso SP, Hiatt WR (2006). Peripheral arterial disease in patients with diabetes. J Am Coll Cardiol 47:921 \200\223929. McDermott MM, Greenland P, Liu K, et al. (2001). Leg symptoms in peripheral arterial diseas e: associated clinical characteristics and functional impairment. JAMA 286:1599. McDermott MM, Kerwin DR, Liu K, et al. (2001). Prevalence and signi \201 cance of unrecogn ized lower extremity peripheral arterial disease in general medicine practice. J Gen Intern Med 16:384 . McDermott MM, Liu K, Greenland P, et al. (2004). Functional decline in peripheral arterial disease: associations with the ankle brachial index and leg symptoms. JAMA 292:453. Murabito JM, D \200\231Agostino RB, Silbershatz H, Wilson WF (1997). Intermittent claudicat ion. A risk pro \201 le from The Framingham Heart Study. Circulation 96:44 \200\22349. Norgren L, Hiatt WR, Dormandy JA, et al. (2007). Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 45:S5 \200\223S67. O \200\231Hare, AM, Katz, R, Shilpak, MG, et al. (2006). Mortality and cardiovascular risk across the ankle- arm index spectrum: results from the Cardiovascular Health Study. Circulation 113:388. Olin JW (2005). Hypertension and peripheral arterial disease. Vasc Med 10:241 \200\223246. FURTHER READING 171 Ouriel, K (2001). Peripheral arterial disease. Lancet 358:1257. Pasternak RC, Criqui MH, Be njamin EJ, et al. (2004). Atherosclerotic vascular disease conference: Writing Group I: epidemiology. Circulation 109:2605. Rimmer, JM, Gennari, FJ (1993). Atherosclerotic renovascular disease and progressive renal failure. Ann Intern Med 118:712. Selvin E, Erlinger TP (2004). Prevalence of and risk factors for peripheral arterial diseas e in the United States: Results from the National Health and Nutrition Examination Survey, 1999 \200\2232000. Circulation 110:738 \200\223743. Smith SC Jr, Milani RV, Arnett DK, et al. (2004). Atherosclerotic vascular disease conferen ce: Writing Group II: risk factors. Circulation 109:2613. Wattanakit K, Folsom AR, Selvin E, et al. (2005). Risk factors for peripheral arterial dise ase incidence in persons with diabetes: The Atherosclerosis Risk in Communities (ARIC) Stud y. Atherosclerosis 180:389 \200\223397. Wildman RP, Muntner P, Chen J, et al. (2005). Relation of in \202 ammation to peripheral a rterial disease in the national health and nutrition examination survey, 1999 \200\2232002. Am J Cardiol 96:1579 \200\2231583. This page intentionally left blank 173 Chapter 4 Valvular heart disease General considerations 174 Acute rheumatic fever 176 Mitral stenosis 179 Mitral regurgitati on 183 Mitral valve prolapse 186 Aortic stenosis 188 Aortic stenosis: management 190 Aortic regurgitation 193 Right heart valve lesions 197 Prosthetic heart valves 200 Prosthetic hea rt valves: complications 203 Infective endocarditis 204 CHAPTER 4 Valvular heart disease 174 General considerations Development Cardiac valves develop from the mesodermal germ layer be tween the fourth and seventh weeks of gestation. Factors affecting embryogen- esis during t his time can in \202 uence valve development, such as infection (rubella) or drugs. Anatomy The human heart contains four valves: two on the left side of the heart (mitral and aortic) and two on the right (tricuspid and pulmonic, or pul- monary) (Fig. 4.1). The mitral and tricuspid valves, also referred to as atrioventricular (AV) valves, are supp orted by a \201 brous skeleton and separate the atrial and ventricular chambers, ensuring unidirectional \202 ow of blood during dias- tole. The mitral valve is composed of two l ea \202 ets (anterior and poste- rior) while the tricuspid valve (as the name implies) con tains three lea \202 ets (anterior, posterior, and septal). Both the mitral and tricuspid valve lea \202 ets are attached by chordae tendinae to papil lary muscles in their respective ventricles, the contrac- tion of which ensures valve compe tency. The aortic and pulmonic valves, also referred to as semilunar valves, separate the left and right ventricles from the aorta and pulmonary artery, respectively, ensuring unidirectiona l forward blood \202 ow during systole. The aortic and pulmonic valves each contain three cusps. GENERAL CONSIDERATIONS 175 Superior vena cava Aorta Pulmonary artery Pulmonary vein Left atrium Right atrium Mitral valve Left ventricle Pulmonary valve Aortic valve Right ventricle Tricuspid valve Inferior vena cava Figure 4.1 Heart valves as viewed from above with the atria removed (top) and in a coronal section (bottom). CHAPTER 4 Valvular heart disease 176 Acute rheumatic fever Epidemiology In the United States and other developed countries, the incidence is 2 to 14 cases per 100,000, with around 10 cases per 1000 school children in de veloping countries. Although it is now rare in the developed world, it still accounts for a lmost half of all cardiac disease in the developing world. Declining incidence in the developed world is likely due to improved economic standards and housing conditions, decreased crowding in houses and schools, improved access to medical c are, and effective antimicrobials, especially penicillin. Those affected are typically children aged 5 \200\22315 years from lower socio- economic cl ass living in crowded conditions; 20% of cases occur in adults. There is no gender differen ce in incidence, but chorea and mitral steno- sis (MS) are more common in females. Pathology \200 \200 It typically occurs several weeks after streptococcal pharyngitis. The most common pathogen is group A beta-hemolytic streptococci (Streptococcus pyogenes serotype M). Antigenic mimi cry is implicated in the pathogenesis as antibodies to carbohydrates in the cell wall (anti -M antibodies) of group A Streptococcus cross-react with proteins in cardiac valves. Time f rom acute streptococcal infection to onset of symptomatic rheumatic fever (RF) is usually 3 \200\2234 weeks. RF is thought to complicate up to 3% of untreated streptococcal sore thro ats. Previous episodes of RF predispose to recurrences. Other areas of cross-reactivity may explain noncardiac \201 ndings (e.g., involvement of connective tissue in joints causing arthritis, caudate nucleus in brain leading to Sydenham \200\231s chorea). RF commonly cau ses a Pericarditis constriction. may cause acute heart failure and arrhythmias. Myocarditis affects the mitral valve (65% \200\22370%), aortic valve (25%), and Endocarditis tricuspid valve (10%, never in isolation), causing acute regurgitation and heart failure but chronic stenosis. Pericardium, perivascular regions of myocardium, and endocardium develop foci of eosinophilic collagen surrounded by lymphocytes, plasma cells, and macrophages called Asch off bodies. \200 \200 pancarditis. rarely causes hemodynamic instability/tamponade or \200 Clinical features \200 \200 \200 Sore throat Fever, abdominal pain, and epistaxis. Migratory large-joint of cases. Duration is <4 weeks at each site. There is severe pain and tenderness in contrast to a mild degree of joint swelling. occurs 1 \200\2235 weeks prior in two-thirds of cases. polyarthritis starting in the lower limbs in 75% ACUTE RHEUMATIC FEVER 177 Pancarditis mitral and aortic regurgitation, and pericarditis. Chorea pharyngitis. Patients exhibit dif \201 culties in writing and speaking, generalized weakness, choreiform moveme nts, and emotional lability. Joints are hyperextended with hypotonia, diminished tendon re \202 exes, tongue fasciculation, and a relapsing grip (alternate increases and decreases i n tension). Full recovery is usually in 2 \200\2233 months. Erythema marginatum and central clearings on the trunk and proximal limbs. It is seen in 5% \200\22313% of cases. It begin s as erythematous, nonpruritic papules or macules that spread outward. It fades and reappea rs in hours and persists throughout the disease course. See Fig. 4.2. Subcutaneous nodules after the onset of pancarditis. They occur mainly over bony surfaces or joint prominences a nd tendons and usually last 1 \200\2232 weeks. There is a risk of overdiagnosing RF in chil dren admitted with fever, soft murmurs, and arthralgia, all of which are common in childhoo d. Evidence for an antecedent streptococcal infection is required for the de \201 nitive d iagnosis \200\224see Box 4.1. occurs in 50% of cases with features of acute heart failure, occurs in 10% \200\22330%, usually occurs 1 \200\2236 months after is an evanescent rash with serpiginous outlines are seen in 0 \200\2238% of cases usually several weeks Treatment \200 Oral penicillin V for 10 days or intramuscular penicillin G (single dose of 1.2 million uni ts) to treat the acute infection. If patient is penicillin allergic, use oral erythromycin, azithromycin, or cephalexin for 10 days. Oral aspirin 4 \200\2238 g daily until ESR and CR P are normal Systemic corticosteroids for 2 \200\2234 weeks for moderate \200\223severe car ditis Standard medical therapy (i.e., diuretics, ACE inhibitors, and digoxin) for heart fai lure \200 \200 Figure 4.2 Erythema marginatum in rheumatic fever. CHAPTER 4 Valvular heart disease 178 Box 4.1 Diagnostic criteria for rheumatic fever (Jones criteria) \200 \200 Evidence of group A streptococcal pharyngitis Either a positive throat culture or rapid str eptococcal antigen test, or an elevated or rising streptococcal antibody titer (samples tak en 2 weeks apart). Plus two major or one major and two minor Jones criteria: Minor criteria \200 \200 \200 \200 Major criteria \200 Polyarthritis \200 Carditis \200 Chorea \200 Erythema marginatu m \200 Subcutaneous nodules Fever Arthralgia Prolonged PR interval Elevated ESR and CRP Prognosis \200 \200 \200 \200 Determined by severity of cardiac involvement. Acute-phase duration is about 3 months in 80 % of cases. Mortality is 1% \200\22310% in developing countries. Recurrence rates are high and are most common in the \201 rst 2 years following acute infection. Chronic valve dise ase occurs in one-third without and two-thirds with recurrent infections. Murmurs resolve i n 50% of cases up to 5 years after index infection. Antibiotic prophylaxis against group A streptococcal infection is used to prevent recurrence of RF. It is usually continued for at least 10 years or until young adulthood. Daily oral penicillin or intramuscularly penicill in injection every 3 \200\2234 weeks are standard regimens. Erythromycin can be used in pen icillin-allergic patients. \200 