CARDIOVASCULAR BOARD REVIEW C. RIMMERMAN, B.P. GRIFFIN, EDITORS A SELF-TEST ON A TOBIAS PEIKERT, MD CRAIG R. ASHER, MD BRIAN P. GRIFFIN CLINICAL Department of Internal Medicine, Department of Cardiovascular Department of Cardiovascular Cleveland Clinic Medicine, Cleveland Clinic Medicine, Cleveland Clinic CASE

Systolic ejection murmur presenting with dyspnea on exertion

43-YEAR-OLD WOMAN was referred to ■ DIFFERENTIAL DIAGNOSIS A the outpatient clinic for OF SYSTOLIC EJECTION MURMUR evaluation of a systolic ejection murmur. Her symptoms at presentation consisted of dysp- Which of the following conditions should nea on exertion, decreased exercise tolerance, 1 not be included in the differential diagno- generalized fatigue, and intermittent palpita- sis of a systolic ejection murmur? tions. Her functional impairment was consis- tent with New York Heart Association ❑ stenosis (NYHA) class 2 to class 3. She had a known ❑ Mitral valve regurgitation cardiac murmur since childhood. In the past ❑ Aortic valve sclerosis she experienced presyncopal episodes and, on ❑ Hypertrophic cardiomyopathy one occasion, syncope. ❑ Subaortic membrane She admits to the social use of cigarettes and alcohol. Her father had coronary Mitral valve regurgitation is the only one of disease and diabetes mellitus, and an uncle the above conditions that does not present had died suddenly of an unknown cause. with a systolic ejection murmur. Keep an open Systolic murmurs are characterized as mind when Physical examination “ejection” (TABLE 1) or “regurgitant”. Systolic Her vital signs were within normal limits. She ejection murmurs are audible only during part evaluating had no carotid or jugular venous disten- of systole, that is, they begin after S1 and end patients with tion. The carotid upstroke was slightly before S2. However, regurgitant murmurs, delayed, with normal volume and without such those caused by mitral valve prolapse, are preexisting pulsus bisferiens (a midsystolic dip). The holosystolic, ie, they are audible throughout diagnoses point of maximum impulse was nondisplaced all of systole: they generally start with S1 and and sustained. Cardiac revealed a end with S2. normal S1 and S2 (P2) and no S3 or S4. A 3/6 The proper evaluation of any systolic systolic ejection murmur with early onset and murmur requires consideration of such fac- harsh crescendo was noted throughout the tors as the location, intensity, timing, con- precordium, with no radiation to the axilla or figuration, character, radiation, change of the neck. The murmur did not change with characteristics with certain maneuvers, and standing, hand-gripping, and the Valsalva associated findings and symptoms (TABLE 2). maneuver. Her were symmetric, and To differentiate aortic valve stenosis from she had no peripheral edema. aortic valve sclerosis it is important to know that patients with aortic valve sclerosis usu- Initial studies ally have no symptoms and that there is no Chest radiography revealed slight car- radiation of the murmur, no change in diomegaly. Baseline character, and no delay or decreased inten- showed sinus rhythm and left ventricular sity of the aortic component of S2. The hypertrophy with repolarization abnormali- murmur is usually brief and soft. ties. To distinguish a fixed stenosis (as in aor-

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T ABLE 1 CASE CONTINUED Prior evaluation and treatment Differential diagnosis at other institutions of systolic ejection murmurs The patient had been evaluated in different Aortic systolic ejection murmurs hospitals before presenting to our institution. Left ventricular outflow tract (LVOT) obstruction Echocardiography and cardiac catheterization Valvular had detected a pressure gradient of 100 mm Hg within the LVOT (the normal pressure Degenerative (tricuspid valve) gradient is zero). The aortic valve was deemed Degenerative (bicuspid valve) morphologically normal with regular excur- Subvalvular aortic stenosis sion, and no evidence of coronary artery dis- Hypertrophic obstructive cardiomyopathy ease had been seen. Fixed (discrete) subvalvular stenosis The patient had been given a diagnosis Supravalvular aortic stenosis of hypertrophic cardiomyopathy, but treat- Aortic dilation Hypertension ment with beta-blockers, calcium channel Aneurysms blockers, and disopyramide and the implan- Coarctation of the aorta tation of a DDDR (dual-chamber, adaptive- Aortic valve sclerosis rate) pacemaker had failed. Holter monitor- Increased aortic flow ing prompted by the syncopal episode had Aortic regurgitation shown frequent premature ventricular con- Anemia tractions and runs of nonsustained ventricu- Thyrotoxicosis lar . Fever Pregnancy ■ LEFT VENTRICULAR Exercise OUTFLOW TRACT OBSTRUCTION Pulmonic systolic ejection murmurs On the basis of the patient’s clinical presenta- Right ventricular outflow tract (RVOT) obstruction tion and the prior echocardiographic and arte- Pulmonic valvular stenosis riographic findings, especially the presence of Infundibular stenosis a pressure gradient between the left ventricu- Supravalvular pulmonic stenosis lar cavity and the LVOT, a diagnosis of LVOT Pulmonary artery dilation Idiopathic obstruction can be made. Pulmonary hypertension What would be the most likely cause of 2 LVOT obstruction in this patient? tic valve stenosis) from a dynamic left ven- ❑ Hypertrophic cardiomyopathy tricular outflow tract (LVOT) obstruction (as ❑ Valvular aortic stenosis in hypertrophic cardiomyopathy), it is ❑ Supravalvular (ie, supra-aortic valve) important to evaluate changes of the murmur stenosis during certain functional maneuvers that ❑ Fixed subvalvular stenosis produce changes in cardiac preload, after- ❑ Aortic coarctation load, and contractility (TABLE 2).1 For exam- ple, standing and the Valsalva maneuver For reasons discussed below, a subvalvular decrease the intensity of the murmur in cause is the most likely in this patient, based patients with aortic valve stenosis, whereas on the history, symptoms, and physical find- they accentuate the murmur in patients with ings. hypertrophic cardiomyopathy. Patients with The differential diagnosis of LVOT a fixed subvalvular stenosis have a preserved obstruction can be divided into three major S2 and carotid upstroke, and the murmur may categories on the basis of the location of the decrease in intensity with the Valsalva obstructing lesion (TABLE 2): supravalvular, maneuver and standing. valvular, and subvalvular.

810 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 9 SEPTEMBER 2001 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. T ABLE 2 Features of the physical examination that help to differentiate the causes of left ventricular outflow tract obstruction

FEATURE VALVULAR SUPRAVALVULAR SUBVALVULAR DISCRETE HYPERTROPHIC SUBVALVULAR STENOSIS CARDIOMYOPATHY

Pulse pressure after Increased Increased Increased Decreased ventricular premature beat Effect of Valsalva maneuver Decreases Decreases Decreases Increases on systolic murmur Murmur of aortic regurgitation Common Rare Sometimes Rare If severe Uncommon Uncommon Common Paradoxic splitting Sometimes Absent Absent Common Ejection click Most, except in Absent Absent Absent cases of calcified valve Maximal thrill and murmur Second right First right Second right Fourth left intercostal space intercostal space intercostal space intercostal space Carotid pulse Reduced Unequal Normal to reduced Brisk, jerky upstroke upstroke upstroke, systolic rebound ADAPTED FROM MARRIOTT HJL. BEDSIDE CARDIAC DIAGNOSIS. PHILADELPHIA: J.B. LIPPINCOTT, 1993:116.

Supravalvular causes of LVOT obstruction require surgical intervention early in child- Supravalvular causes of LVOT obstruction are hood, which makes them an unlikely diagno- aortic coarctation, fixed supravalvular stenosis, sis in our patient.2,3 Occasionally, severe fibrous membranes, and fibromuscular ridges. familial hyperlipidemia leads to fatty deposi- Aortic coarctation and fixed supravalvu- tion above the aortic valve and to stenosis at lar stenosis are congenital conditions that usu- that point. ally become symptomatic and are diagnosed earlier in life. Aortic coarctation is caused by Valvular causes of LVOT obstruction a fibromuscular ridge in the location of the The most frequent valvular abnormality former ductus arteriosus distal to the origin of resulting in aortic stenosis is degenerative dis- the left subclavian artery. Symptoms at pre- ease. Depending on the underlying anatomy, sentation usually include hypertension aortic stenosis becomes hemodynamically sig- involving the upper extremities and delayed nificant in different age groups. The most and decreased pulses in the lower extremities. common cause of aortic stenosis in people Aortic coarctation is a cause of secondary under age 55 is a congenitally abnormal aortic hypertension. In this particular case, aortic valve. Often, the valve is still pliable at the coarctation is very unlikely since hyperten- time of presentation, resulting in an ejection sion is absent and the peripheral pulses are click preceding the systolic ejection murmur. normal on physical examination. The most common congenital valvular Fibrous membranes and fibromuscular cause of LVOT obstruction is a bicuspid aortic ridges can also occur immediately above the valve caused by congenital commissural aortic sinuses and often lead to hypoplasia of fusion. This condition may lead to significant the ascending aorta. However, these forms of hemodynamic compromise, with severe fusion aortic stenosis are rare. They generally and calcification that causes valvular aortic become symptomatic and subsequently stenosis requiring early surgical intervention.

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Rheumatic aortic stenosis is now uncom- ing contact of the valve with the interventric- mon. Rheumatic fever results in thickening ular septum. A distinct feature of this particu- and fusion of the aortic cusps and commissures lar form of LVOT obstruction is its dynamic leading to aortic stenosis, regurgitation, or character: ie, the severity of the LVOT both. In this setting aortic disease is almost obstruction changes in response to variation always associated with mitral valve abnormal- in hemodynamic variables such as cardiac pre- ities. The typical age of onset of symptoms is load, afterload, and inotropic stimulation. the fourth through sixth decades of life, usual- In many patients, medical treatment with ly 10 to 20 years after an episode of acute negative inotropes such as beta-blockers, cal- rheumatic fever. In our patient, the presence cium channel blockers, or disopyramide may of the murmur early in life and the echocar- improve or alleviate the symptoms. In some diographic findings make this diagnosis very patients, however, the dynamic LVOT unlikely. obstruction responds only to ablation of the In people age 55 and older, aortic stenosis septal muscle at surgery (myectomy) or with is usually caused by degenerative changes alcohol injection of a septal coronary artery involving a tricuspid aortic valve, resulting in (alcohol septal ablation).8,9 progressive calcification and restriction. Risk Discrete subvalvular stenosis (fixed factors contributing to the progression of dis- LVOT obstruction). In patients with a fixed ease are similar to risk factors for coronary LVOT obstruction, severe ventricular hyper- artery disease and include hyperlipidemia and trophy may result and may simulate the clini- hypertension.2–7 cal and echocardiographic picture of hyper- In our patient a problem with the valve trophic cardiomyopathy. Careful two-dimen- itself appears to be very unlikely, since the aor- sional and Doppler echocardiography is essen- tic valve appeared normal on echocardiogra- tial to distinguish hypertrophic cardiomyopa- phy. The most likely type of stenosis in our thy from a fixed LVOT obstruction. Often patient is subvalvular. transesophageal echocardiography (TEE) is necessary to adequately exclude a membrane Valsalva Subvalvular causes of LVOT obstruction in the LVOT as the cause of a fixed obstruc- and other Two subvalvular conditions are known to cause tion (as in fixed subaortic stenosis).10 subaortic LVOT obstruction: hypertrophic car- Fixed subaortic stenosis may occur as long- maneuvers diomyopathy and discrete subaortic stenosis. segment (tunnel) stenosis or short-segment caused no Hypertrophic cardiomyopathy is a genet- (fibromuscular ring or membrane) stenosis. ic cardiac disorder with a prevalence estimat- change in the ed at 1:500. It is caused by several distinct Pathophysiology of discrete subaortic stenosis murmur genetic mutations resulting in hypertrophy The pathophysiology of discrete subaortic and myocardial disarrangement. Involvement stenosis is not completely understood. On one of the interventricular septum is predominant. hand, a genetic component is reflected by the The myocytes are of bizarre shapes and are familial incidence of the disease and the pres- arranged in a chaotic pattern oriented in ence of a similar condition in Newfoundland oblique and perpendicular angles. These cellu- dogs. In addition, more than 50% of patients lar abnormalities are thought to be the sub- have an association with other congenital strate for cardiac arrhythmias. Ventricular heart lesions, including coarctation, bicuspid arrhythmias constitute the major cause of aortic valve, mitral valve abnormalities, and death in patients with hypertrophic cardiomy- ventricular septal defects. On the other hand, opathy. subaortic stenosis is rarely seen in infancy, as Dynamic LVOT obstruction. In a subgroup would be expected. Current thinking favors an of patients with hypertrophic cardiomyopathy, acquired lesion that develops based on a of LVOT obstruction genetic predisposition. Gewillig et al11 sug- dominate the clinical picture. In these gested that an abnormal flow pattern, in con- patients the LVOT compromise appears to be junction with endothelial damage and a coex- due to septal hypertrophy resulting in systolic istent genetic predisposition, likely results in anterior motion of the mitral valve and caus- the development of the typical fibromuscular

812 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 9 SEPTEMBER 2001 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. obstruction. Further evidence that the condi- tion is acquired is the significant recurrence rate after surgical resection of the lesion. The lower recurrence rate seen after combined resection of the subaortic membrane and myectomy is thought by some to be due to an alteration in the intraventricular flow pattern by the myectomy. Associated complications include an increased risk of (enough to war- rant antibiotic prophylaxis), severe left ven- tricular hypertrophy, and damage to the aortic valve by the high-velocity jet in the LVOT, resulting in . This is thought to be caused by mechanical damage due to the stenotic jet.

CASE CONTINUED Consideration of a fixed subaortic obstruction FIGURE 1. Transthoracic echocardiogram, parasternal long- Our patient’s prior diagnosis of hypertrophic axis view. Dotted arrow points to LVOT subaortic cardiomyopathy had been based on her clini- membrane. Solid arrow identifies the position of the cal presentation and echocardiographic and normal aortic valve. arteriographic findings. Since therapeutic attempts including medical therapy and dynamic character of the LVOT obstruction. implantation of a dual-chamber pacemaker TEE also provides information regarding the had been unsuccessful, the possibility of a fixed attachment of subaortic lesions (mitral valve, subaortic obstruction needs to be considered. septum), the degree of obstruction of the aor- tic valve, and the amount of aortic regurgita- Failure of drug ■ SELECTING THE APPROPRIATE tion, and aids the identification of associated and pacemaker DIAGNOSTIC TEST cardiac abnormalities. Cardiac catheterization is an invasive therapy hint at Which of the following diagnostic tests procedure capable of defining the area of a fixed LVOT 3 would be appropriate to clarify the obstruction angiographically and of measuring patient’s diagnosis? the severity of the pressure gradient; however, obstruction it provides less anatomic detail than TEE. ❑ Transesophageal echocardiography (TEE) Still, it is helpful in the preoperative evalua- ❑ Cardiac catheterization tion of the coronary and can be com- ❑ Cardiac magnetic resonance imaging (MRI) bined with functional maneuvers. ❑ All of the above Cardiac MRI is a very helpful noninva- sive test for the delineation of cardiac anato- All of the above listed tests could contribute my, but it provides less information about the to the clarification of the diagnosis in this par- severity of the pressure gradient and its ticular patient. However, the most appropri- response to maneuvers. ate next step would be TEE. TEE allows both anatomic and physiolog- CASE CONTINUED ic evaluation of an LVOT obstruction regard- Findings on echocardiography less of the patient’s body habitus. For the The patient underwent two-dimensional physiologic evaluation it provides the oppor- transthoracic echocardiography at our institu- tunity to perform maneuvers such as the tion. This suggested an LVOT obstruction Valsalva maneuver, to use vasodilators such as (peak gradient 93 mm Hg; mean gradient 55 amyl nitrate, or to apply positive inotropic mm Hg), 3+ aortic regurgitation, left ventric- agents such as isoproterenol to assess the ular hypertrophy resulting in thickening of

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the interventricular septum, and normal glob- ent (> 50 mm Hg mean), evidence of damage al left and right ventricular function. TEE to the aortic valve (such as aortic regurgita- detected a subaortic membrane and confirmed tion), or symptoms. the other transthoracic echocardiographic findings (FIGURE 1). On cardiac catheterization, CASE CONTINUED no evidence of coronary artery disease was Results of surgical treatment found. The patient underwent surgical resection of the subaortic membrane and septal myectomy. ■ WHEN IS SURGICAL INTERVENTION Postoperative transthoracic echocardiography APPROPRIATE? revealed resolution of the LVOT obstruction with a dynamic gradient of 18 mm Hg and 2+ Based on current knowledge, when is sur- aortic regurgitation. The histologic evaluation 4 gical intervention appropriate? of the resected tissue revealed hypertrophied myocardium but no myocardial disarray ❑ Immediately after diagnosis of the stenosis indicative of hypertrophic cardiomyopathy. ❑ When the LVOT mean pressure gradient is more than 50 mm Hg in a patient with ■ LESSONS LEARNED no symptoms ❑ When symptoms develop It is very important to keep an open mind ❑ When complications occur, such as aortic when evaluating patients carrying preexisting insufficiency or bacterial endocarditis diagnoses who are referred for treatment ques- tions. A poor response to the standard thera- The timing of surgical correction is still con- peutic regimens in a patient with presumed troversial. Given the risk of recurrence, early hypertrophic obstructive cardiomyopathy intervention in this condition might be asso- should always raise suspicion of an incorrect ciated with multiple reoperations. Certain diagnosis. In the case of our patient, a fixed experts propose surgery immediately after the LVOT obstruction needed to be excluded. diagnosis of the stenosis,12,13 whereas others It is also important to remember that establish specific cut-off points for the LVOT hypertrophic cardiomyopathy is not the only gradient for surgical intervention in asympto- disease process resulting in a dynamic LVOT matic patients.14,15 Experts agree that surgery obstruction: it may also occur after mitral valve is required in patients who have symptoms.16 repair or in patients who have left ventricular Current thinking favors an early approach to hypertrophy and a small ventricular cavity who surgery if the patient has a high pressure gradi- are dehydrated, eg, after a surgical procedure.

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