Circulation Cardiovascular Case Series

Circulation Cardiovascular Case Series Asymptomatic Severe Aortic Stenosis Silence of the Lambs? Ravi V. Shah, MD; Nihar R. Desai, MD, MPH; Patrick T. O Gara, MD Forward Information about a real patient is presented in stages (boldface type) to an expert clinician (Dr Patrick O Gara), who responds to the information, sharing his or her reasoning with the reader (regular type). A Discussion by the authors follows. A 62-year-old man with a past medical history presents to the cardiology clinic for evaluation after a routine echocardiogram obtained for evaluation of palpitations. His clinical history is remarkable for infrequent self-terminating episodes of regular rapid heartbeat over the last 2 months. The events are not associated with chest discomfort, dyspnea, lightheadedness, dizziness, or flushing. He denies any symptoms of rest or exertional chest discomfort or dyspnea, recent syncope or presyncopal sensations, or paroxysmal nocturnal dyspnea. He states that he has been reducing his physical activity over the last several years because of fatigue. His past medical history is remarkable for hyperlipidemia and erectile dysfunction. He has no drug allergies. His medications include a multivitamin, simvastatin, and tadalafil. He smokes 1 pack of cigarettes per day and has a >30 pack-year smoking history. He neither drinks alcohol nor uses illicit drugs. He is a retired store clerk. Dr Patrick O Gara: The history does not provide the context in which the episodes of self-terminating, rapid, regular heart action occur. It would be important to establish their relation to activity, meals, time of day, caffeine intake, cigarette use, or ingestion of any over-the-counter medications or supplements. Asking the patient to tap out the cadence of his heartbeat could be helpful. His limited physical activity may mask appreciation of early symptoms of underlying cardiovascular disease and should serve as a warning that the history may be misleading or falsely reassuring. Specific reasons for his fatigue should be explored, including the possibilities of insomnia, sleepdisordered breathing, depression, anemia, hypothyroidism, smoking-related pulmonary disease, and symptoms suggestive of a chronic inflammatory disorder. A family history of arrhythmia, sudden cardiac death, premature coronary artery disease (CAD), and valvular or congenital heart disease should be queried. The aggregate symptoms are not indicative of a specific cardiovascular disorder, although his age, sex, dyslipidemia, cigarette habit, and erectile dysfunction as well as the fact that he is referred after performance of an echocardiogram raise concerns for coronary artery and/or structural heart disease. The physical examination should be directed accordingly. On his physical examination, his pulse is 75 bpm, his blood pressure is 150/70 mm Hg in both arms, and his respirations are 16 breaths per minute. He appears well. His jugular venous pressure is 8 cm water. His carotid upstrokes are nondelayed with respect to the point of maximal impulse and are of normal volume. He has a normal S 1 and a soft S 2. He has a III/VI late-peaking systolic crescendo-decrescendo murmur at the right upper sternal border radiating into his right neck and clavicle. His point of maximal impulse is not displaced. There is an S 4 gallop but no pericardial rub. His abdomen is benign without pulsatile masses or bruits. His femoral pulses and pedal pulses are 2, full, and without delay. There are no femoral bruits. He has no peripheral edema. Dr O Gara: Pertinent findings include the regular heart rhythm at rest, mildly elevated systolic blood pressure with a wide pulse pressure, and systolic heart murmur, the attributes of which are most consistent with aortic stenosis (AS). Although the carotid upstrokes are described as normal, other findings suggest that the AS may be significant, including the late-peaking nature of the murmur, diminished intensity of S 2, and the S 4 (presystolic) gallop. It is not clear whether systolic hypertension may coexist or whether a murmur of aortic regurgitation may have been missed to explain, in part, his wide pulse pressure. The amplitude and contour of the carotid upstroke are notoriously less reliable as indicators of AS severity in elderly hypertensive patients, although this patient is only 62 years of age and may not have hypertension. The history should readdress whether he had been informed of a heart murmur in the past and focus on the 3 most common From the Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School (R.V.S.), and Cardiovascular Medicine Division, Brigham and Women s Hospital, Harvard Medical School (N.R.D., P.T.O.), Boston, Mass. If you would like to comment on this article, please go to http://circ.ahajournals.org and submit a comment by selecting the Submit a Comment link on the right-hand side of the page. Correspondence to Patrick T. O Gara, MD, Division of Cardiovascular Medicine, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02115, (E-mail pogara@partners.org); or Ravi V. Shah, MD, Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, (E-mail rvshah@partners.org). (Circulation. 2010;122:1734-1739.) 2010 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.110.989152 1734

Shah et al Asymptomatic Severe Aortic Stenosis 1735 Figure 1. The 12-lead ECG showing left ventricular hypertrophy with nonspecific ST-T wave abnormalities. causes of AS, including bicuspid aortic valve disease and its variants; degenerative, calcific AS; and rheumatic AS. Even at 62 years of age, a congenital cause for his AS should be considered, as should calcific, degenerative disease affecting a trileaflet valve, especially given the shared atherosclerotic risk factors of dyslipidemia and smoking. Rheumatic disease, especially in the absence of examination findings of mitral valve involvement, would be least likely. More directed questioning about his fatigue is needed to determine whether he may be describing some degree of effort intolerance. The family history should be repeated with attention to aortic and/or aortic valve disease. The pulse examination is not supportive of a diagnosis of coarctation, but the clinician should be alert to the coexistence of bicuspid aortic valve and ascending aortic aneurysm disease. Initial investigations should include an ECG and transthoracic echocardiogram. A chest radiographic is not routinely recommended in the absence of signs of heart failure. Laboratory studies should include a complete blood count, fasting glucose, lipids, electrolytes, renal function, and urinalysis. His ECG (Figure 1) demonstrates sinus rhythm with left ventricular hypertrophy and nonspecific ST-T wave abnormalities. His initial laboratory examination (a full complete blood count and electrolyte and renal panel) is within normal limits. His total cholesterol is 201 mg/dl, with a low-density lipoprotein fraction of 142 mg/dl and high-density lipoprotein fraction of 37 mg/dl. A routine chest radiograph is normal, and his B-type natriuretic peptide is 105 pg/ml. Review of his echocardiogram reveals a left ventricular ejection fraction of 60% to 65% with concentric left ventricular hypertrophy. His right ventricular function is normal. His aortic valve is trileaflet with severe leaflet thickening, a fixed right coronary cusp, and restricted left and noncoronary cusps (Figure 2). There is severe aortic valve annular calcification. The peak velocity by continuous-wave Doppler across the aortic valve is 4.4 m/s. The peak transaortic pressure gradient is 77 mm Hg, with a mean gradient of 41 mm Hg and an aortic valve area calculated as 0.8 cm 2, consistent with an echocardiographic diagnosis of severe aortic valve stenosis (Figure 3). There is mild to moderate aortic insufficiency (Figure 4). The aortic root at the sinuses of Valsalva is 3.5 cm, which enlarges to 4.4 cm in the proximal ascending aorta, with significant aortic atheroma. Trace mitral regurgitation is noted. Figure 2. Parasternal long-axis view demonstrating severe aortic annular calcification and valve leaflet thickening (arrow) consistent with AS.

1736 Circulation October 26, 2010 Figure 3. Continuous-wave Doppler recording across the aortic valve in an apical 5-chamber view. Dr O Gara: The transthoracic echocardiogram findings show severe, trileaflet AS with mild to moderate aortic regurgitation, normal left ventricular systolic function, and mild concentric left ventricular hypertrophy. In addition, the aortic annulus is heavily calcified, and the ascending aorta is enlarged with extensive atheromatous change. These last 2 findings are not typical of isolated valvular AS, suggest a more aggressive form of degenerative/inflammatory aortic and aortic valve disease, and would imply a higher-than-usual risk for coexistent CAD. Index transthoracic echocardiogram predictors of event-free survival in asymptomatic AS include the peak jet velocity and the extent of valvular calcification. The annual increase in peak jet velocity is also of prognostic importance for patients initially followed up conservatively with surveillance imaging. The absolute B-type natriuretic peptide level is nondiscriminatory, although there are emerging data on the inclusion of serum B-type natriuretic peptide levels in a risk score with peak jet velocity for patients with asymptomatic AS. In addition to smoking cessation, guideline-recommended lipid management, blood pressure control, and aspirin therapy, the next step in management would be an objective assessment of his baseline functional capacity and ischemic threshold. The patient s history does not allow a confident appraisal of these important factors, which may dictate surgical intervention at this stage in the natural history of his disease. Several studies have substantiated the safety of treadmill or bicycle exercise, when performed with a physician in attendance, in patients with asymptomatic AS with preserved left ventricular systolic function; however, every precaution should be taken. The exercise protocol should be individually tailored to reflect the activity levels achieved during daily living. Outcome variables of interest include early-onset symptoms, systolic blood pressure response, emergence of ventricular arrhythmias, and to a lesser extent, the magnitude and duration of ST-segment depression. An abnormal exercise response predicts reduced Figure 4. Apical 3-chamber view with color Doppler in the systolic phase (left) and diastolic phase (right) demonstrating turbulent flow through the aortic valve and aortic insufficiency (arrows).

Shah et al Asymptomatic Severe Aortic Stenosis 1737 Figure 5. Right anterior oblique caudal (left) and cranial (right) views of the left coronary artery. Arrows indicate disease of the left main coronary artery (left) and left anterior descending artery (right). event-free survival. Exercise imaging is not routinely considered necessary for assessment of the patient with AS. Continuous-wave Doppler echocardiographic measurement of the change in mean gradient from rest to peak exercise, however, may provide prognostic information. The specificity of regional perfusion and wall motion abnormalities for the diagnosis of CAD is reduced in patients with severe AS and left ventricular hypertrophy. Although normalization of ascending aortic diameter to body size may be useful for clinical decision making, guideline recommendations for surgical management are still based largely on absolute dimensions, and practice patterns vary widely. Enlargement to 4.4 cm would generally not constitute an indication for repair in the setting of atherosclerotic disease, either at the time of aortic valve replacement (AVR) with or without coronary artery bypass graft surgery or in isolation; however, concomitant ascending aortic replacement may be necessary because of advanced atherosclerotic involvement and inability to cannulate safely. He is referred for a standard Bruce protocol treadmill test under careful supervision. He exercises to 4 minutes 43 seconds, stopping because of dizziness. His blood pressure is 140/70 mm Hg at rest and 125/ 60 mm Hg at peak exercise; his heart rate increases from 70 to 110 bpm. He has 1.5-mm downsloping ST depression in the inferior and lateral leads at peak exercise, returning to baseline by 45 seconds of recovery. He does not experience any arrhythmia during or after exercise, and his symptoms abate within 5 minutes of exercise termination. He does not experience syncope. Dr O Gara: The exercise test results are grossly abnormal with respect to the early onset of limiting symptoms in association with a significant fall in systolic blood pressure. The ECG changes are less specific. The exercise response is worse than would be expected on the basis of his AS alone. Although no single absolute valve area or mean gradient defines severe AS with great precision in any individual patient with preserved systolic function, the echocardiographic findings place him just below the threshold at which one would confidently predict that isolated AS accounts for his poor performance. Coronary angiography is the next appropriate step in his evaluation. Hemodynamic assessment of his AS and left ventricular function is not necessary, given the tight correlation between Doppler and catheter-based assessment of aortic valve mean gradient and area, as well as the potential for embolic complications when crossing a stenotic aortic valve. Hemodynamic assessment is usually reserved for those patients in whom there is a discrepancy between clinical and transthoracic echocardiogram findings. He undergoes diagnostic coronary angiography and is found to have a 50% distal left main coronary stenosis and stenoses in the left anterior descending coronary artery (Figure 5). The right coronary artery is free of obstructive disease. The aortic valve is not directly assessed hemodynamically. Dr O Gara: Referral for AVR plus coronary artery bypass graft surgery, with intraoperative evaluation of the ascending aorta, is indicated. Both significant AS and CAD contribute to his demonstrated effort intolerance. The American College of Cardiology (ACC) and American Heart Association (AHA) 1 (the Table) and the European Society of Cardiology guidelines for the management of patients with valvular heart disease provide several Class I, IIa, and IIb indications (all Level of Evidence C) for AVR in patients with asymptomatic AS and an abnormal response to exercise. Although these recommendations were designed to apply to patients with isolated severe AS, the majority of older adults with severe, degenerative AS have CAD, which may, in turn, influence outcomes. Concomitant revascularization is routinely recommended for coro- Table. Indications for AVR in Asymptomatic Severe AS 1 Class I Class IIb Patients undergoing cardiac surgery for other indications (coronary artery bypass graft surgery or aortic surgery) Left ventricular ejection fraction 50% Abnormal hemodynamic response to exercise (symptoms or asymptomatic hypotension) High probability of rapid progression (age, calcification, concomitant CAD) Asymptomatic very severe AS (transaortic jet velocity 5 m/s, mean gradient 50 mm Hg, aortic valve area 0.6 cm 2 ) when operative mortality is 1%

1738 Circulation October 26, 2010 nary artery stenosis severity 70% even when the relationship of the CAD to symptoms is not readily apparent. Consideration of either percutaneous balloon valvuloplasty or transcatheter aortic valve implantation would not be appropriate in this low-risk individual. The patient undergoes coronary artery bypass graft surgery with bioprosthetic aortic valve replacement and left internal mammary artery to the left anterior descending. His postoperative course is complicated by atrial fibrillation, which is treated with a brief course of oral amiodarone therapy and reversion to sinus rhythm. Dr O Gara: Increasing numbers of informed patients in this age group are opting for bioprosthetic valve replacement, largely predicated on the inconvenience and hazards associated with anticoagulation. Current-generation bioprosthetic valves are more durable than their predecessors, and the risks of reoperation have declined over time. Medical therapy to extend the lifespan of tissue valves is lacking. Postoperative atrial fibrillation complicates the course of as many as 30% to 40% of patients after valve plus coronary artery bypass graft surgery and may obligate this patient to a limited (3-month) course of anticoagulation. Most surgical centers routinely provide aspirin alone to bioprosthetic AVR patients without another indication for anticoagulation therapy. The patient has done well postoperatively and has increased his functional capacity, no longer feeling fatigued. Dr O Gara: The patient should be seen for first postoperative evaluation 2 to 3 weeks after discharge to include progress review, medication reconciliation, referral for cardiac rehabilitation, continued discussion of the principles and goals of secondary prevention, and return to sexual activity. An index postoperative echocardiogram is recommended at 6 to 12 weeks after surgery or earlier for any clinical change. Lifelong medications will include aspirin, a statin, and appropriate antihypertensive therapy. It is likely that he was discharged taking a -adrenoceptor blocker for rhythm management, but other medication choices for blood pressure control are likely to be more appropriate longer term. Discussion Although symptomatic severe AS represents a Class I indication for surgical AVR, 1 AVR in the management of asymptomatic severe AS is a source of ongoing clinical controversy. The decision to intervene in patients with asymptomatic severe AS balances the risk of a prosthetic valve against the risk of sudden cardiac death ( 1%/y). 1 Currently, consideration of AVR in patients with asymptomatic severe AS by the ACC/AHA 2006 practice guidelines involves abnormal resting left ventricular function and hemodynamic responses to closely supervised treadmill exercise testing. 1 Recent data have suggested a role for serial noninvasive markers of disease progression, including absolute and yearly changes in transvalvular Doppler jet velocity 2,3 and valve calcification, 4 as predictors of key clinical events, including death and surgical AVR. Over the past 10 years, there has been significant interest in the safety and predictive value of treadmill exercise testing in asymptomatic severe AS. 2,5 8 A substantial body of evidence demonstrates the safety of closely monitored treadmill exercise testing in patients with truly asymptomatic AS, which currently carries a Class IIb indication in the ACC/AHA guidelines. 1 Although studies of exercise testing in patients with asymptomatic severe AS have been small, the absolute severity of AS (as assessed by severe reduction in aortic valve area, 0.6 cm 2 ), symptoms during modified Bruce exercise testing, or an abnormal exercise test result (defined as ST-segment depression, ventricular arrhythmia, or failure to augment systolic blood pressure 20 mm Hg) have emerged as consistent predictors of outcome in this disease. 5 7 Indeed, in a small study of asymptomatic severe AS, only patients with abnormal exercise test results experienced sudden death in follow-up. 5 As a result, surgical AVR in patients with abnormal exercise results (defined as a hypotensive response to exercise or symptoms) is considered a Class IIb indication in the current version of the ACC/AHA valvular heart disease guidelines. 1 With regard to lesion severity, several additional markers of disease progression and subsequent need for AVR have been recently identified. In a small study of patients with severe AS, asymptomatic patients with symptoms on follow-up have higher baseline N-terminal pro-b-type natriuretic peptide levels, 9 although the utility of natriuretic peptides in the decision to pursue AVR is not well studied. Valve calcification, 4 absolute and changes in transvalvular jet velocity, 2,3 and absolute AS severity 10 are also predictive of outcome. A recent study by Rosenhek et al 10 that investigated 116 patients with asymptomatic but very severe AS (defined as a peak transvalvular jet velocity 5.0 m/s) reported a direct relationship between jet velocity and survival free of cardiac death or AVR that was independent of absolute valve area. The relationship between symptom-free survival and transvalvular velocities has also been confirmed at lower transaortic velocities. 3 On balance, clinical vigilance is mandatory in patients with asymptomatic severe AS, even in the setting of clinical, echocardiographic, or biomarkers of risk. Carefully performed exercise treadmill testing and examination of valve morphology and hemodynamics via echocardiography are crucial. Patients with abnormal left ventricular function at rest (left ventricular ejection fraction 50%) or abnormal exercise testing should be considered for AVR. In the future, novel modalities of imaging cardiac fibrosis (eg, cardiac magnetic resonance) and novel biomarkers of myocardial failure and remodeling will likely be integrated with traditional valve imaging and hemodynamic severity in the evaluation of patients with asymptomatic severe AS for AVR. Furthermore, the advent of percutaneous techniques for AVR will likely change the risk landscape for intervention in asymptomatic severe AS. Until that time, careful clinical history and examination and frequent

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