Open Access: Full open access to
`this and thousands of other papers at
`http://www.la-press.com.
`
`Clinical Medicine Insights:
`Cardiology
`
`Supplement: Structural Heart Disease: Research and Practice in Coronary, Structural, Adult Congenital and
`Peripheral Vascular Cardiology
`Diagnosis and Management of Valvular Aortic Stenosis
`Matthew J. Czarny and Jon r. resar
`Cardiology Division, Department of Medicine, The Johns Hopkins Hospital, Baltimore, MD, USA.
`
`AbstrAct: Valvular aortic stenosis (AS) is a progressive disease that affects 2% of the population aged 65 years or older. The major cause of valvular AS
`in adults is calcification and fibrosis of a previously normal tricuspid valve or a congenital bicuspid valve, with rheumatic AS being rare in the United States.
`Once established, the rate of progression of valvular AS is quite variable and impossible to predict for any particular patient. Symptoms of AS are generally
`insidious at onset, though development of any of the three cardinal symptoms of angina, syncope, or heart failure portends a poor prognosis. Management
`of symptomatic AS remains primarily surgical, though transcatheter aortic valve replacement (TAVR) is becoming an accepted alternative to surgical aortic
`valve replacement (SAVR) for patients at high or prohibitive operative risk.
`Keywords: valvular aortic stenosis, surgical aortic valve replacement, transcatheter aortic valve replacement, balloon aortic valvuloplasty, aortic
`stenosis therapy
`
`SuPPleMent: structural heart disease: research and Practice in Coronary, structural, adult Congenital and Peripheral Vascular Cardiology
`CitAtion: Czarny and resar. diagnosis and Management of Valvular aortic stenosis. Clinical Medicine Insights: Cardiology 2014:8(s1) 15–24
`doi: 10.4137/CMC.s15716.
`ReCeiVeD: april 14, 2014. ReSubMitteD: June 3, 2014. ACCePteD foR PubliCAtion: June 10, 2014.
`ACADeMiC eDitoR: thomas Vanhecke, editor in Chief
`tYPe: review
`funDing: authors disclose no funding sources.
`CoMPeting inteReStS: JRR is a principal investigator for Medtronic CoreValve studies and reports research grants from Medtronic. MJC reports no potential conflicts of interest.
`CoPYRigHt: © the authors, publisher and licensee libertas academica limited. this is an open-access article distributed under the terms of the Creative Commons CC-By-nC 3.0
`license.
`CoRReSPonDenCe: mczarny@jhmi.edu
`this paper was subject to independent, expert peer review by a minimum of two blind peer reviewers. all editorial decisions were made by the independent academic editor. all authors
`have provided signed confirmation of their compliance with ethical and legal obligations including (but not limited to) use of any copyrighted material, compliance with ICMJE authorship
`and competing interests disclosure guidelines and, where applicable, compliance with legal and ethical guidelines on human and animal research participants. Provenance: the authors
`were invited to submit this paper.
`
`Introduction
`is a hemodynamically significant
`Aortic stenosis (AS)
`narrowing of the outlet of the left ventricle with multiple
`potential etiologies, whereas aortic sclerosis is a thickening or
`calcification of the aortic valve without obstruction to left ven-
`tricular outflow. Depending on the level of the obstruction,
`AS is classified as valvular, sub-valvular, or supra-valvular.
`This article reviews the etiology, pathophysiology, diagnosis,
`and management of valvular AS in adults.
`The prevalence of valvular AS in the population aged
`65 years or older is approximately 2%, while another 25–30%
`have aortic sclerosis.1,2 A normal aortic valve area is approxi-
`mately 3–4 cm2, and symptoms of AS tend to develop when
`the aortic valve area is 1 cm2 or less. The severity of AS, which
`will be discussed in detail later in this article, is graded by
`the criteria listed in Table 1. While congenital malformation
`of the aortic valve and rheumatic heart disease predispose
`
`to aortic valve calcification and stenosis, senile calcification
`of a previously normal trileaflet valve is an important and
`frequent cause of valvular AS.
`The normal aortic valve is a trileaflet structure located at
`the junction between the left ventricular outflow tract and the
`aortic root. The leaflets are composed of three distinct layers,
`which from the aortic to ventricular surface are the fibrosa,
`spongiosa, and ventricularis. This leaflet structure is covered
`on both the ventricular and aortic surfaces by endothelium
`in continuity with both the ventricular endocardium and the
`aortic endothelium. Each layer of the aortic valve has a dis-
`tinct structure and function: the fibrosa contains circumfer-
`entially oriented collagen fibers, which provide most of the
`strength of the leaflets; the spongiosa is found at the bases of
`the leaflets, contains mucopolysaccharides, and functions to
`resist compressive forces and facilitate movements between
`the fibrosa and ventricularis during leaflet motion; and the
`
`CliniCal MediCine insights: Cardiology 2014:8(s1)
`
`15
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`

`Czarny and Resar
`
`table 1. Criteria for grading the severity of as by aha/aCC30 and european association of echocardiography/american society of
`echocardiography guidelines.29
`
`Peak aortic jet velocity (m/s)
`Mean pressure gradient (mmhg)
`aortic valve area (cm2)
`indexed aortic valve area (cm2/m2)
`dimensionless index*
`
`MilD
`2.0–2.9
`,20
`.1.5
`.0.85
`.0.50
`
`MoDeRAte
`3.0–3.9
`20–39
`1.0–1.5
`0.60–0.85
`0.25–0.50
`
`SeVeRe
`$4.0
`$40
`#1.0
`,0.60
`,0.25
`
`VeRY SeVeRe
`$5.0
`$60
`−
`−
`−
`
`note: *The dimensionless index is defined as VTIaV/VtilVot or VaV/VlVot, where Vti is the velocity–time integral and V is the peak velocity.
`
`ventricularis contains radially oriented elastin and contributes
`to the flexibility of the leaflets. Valve interstitial cells are found
`in each of these layers and have distinct sub-populations that
`regulate homeostasis within the valve leaflets.3–5 The entire
`right coronary leaflet and most of the left coronary leaflet arise
`from ventricular myocardium, while part of the left coronary
`leaflet and the majority of the non-coronary leaflet are in conti-
`nuity with the anterior leaflet of the mitral valve. Of particular
`relevance to any discussion of aortic valve pathology and its
`invasive treatment is the fact that there is no singular “aortic
`annulus.” Rather, there are three rings near the aortic valve.
`From most ventricular to most aortic in location, these are: the
`ring formed by the basal attachments of the aortic valve leaflets,
`the anatomic ventriculoarterial junction, and the sinotubular
`junction. The aortic valve leaflets are attached in a “crown-like”
`ring spanning the distance between the basal attachments
`and the sinotubular junction, and it is this ring that is gener-
`ally referred to as the surgical annulus. The coronary arteries
`usually arise below the sinotubular junction, but occasionally
`arise above. Finally, and of major clinical importance, the left
`bundle branch runs just inferior to and between the right coro-
`nary cusp and the non-coronary cusp of the aortic valve.6
`Development of AS from a previously normal valve pro-
`gresses over decades and begins with subclinical inflammation,
`advances through a stage of fibrosis and thickening of the valve,
`and eventually results in valvular calcification. Inflammation
`may develop as a result of damage to the valvular endothelium
`due to abnormal flow in a tricuspid or congenitally malformed
`aortic valve, due to chronic inflammation resulting from rheu-
`matic heart disease, or from any of a number of other causes.
`Regardless of predisposing or initiating factors, the vast major-
`ity of stenotic aortic valves in adults are heavily calcified by the
`time they cause symptoms of AS. As the aortic valve becomes
`progressively calcified, the leaflets become less mobile, the aor-
`tic valve orifice becomes increasingly stenotic, and the normal
`flow of blood from the heart is progressively obstructed.
`While the development of AS was once thought to be
`a passive process, we now realize that the aortic valve is a dynamic
`environment involving a complex interplay between valvular
`endothelial cells, valve interstitial cells, inflammatory cells, and
`the extracellular matrix.3–5 However, the pathophysiological
`mechanisms underlying the development and progression
`
`16
`
`CliniCal MediCine insights: Cardiology 2014:8(s1)
`
`of AS remain poorly understood. There is marked similarity
`between the histopathological features of AS and those of
`atherogenesis, including initial endothelial damage, the
`deposition and oxidization of lipid-rich particles at these vul-
`nerable sites, neoangiogenesis, chronic inflammation, and
`eventual calcification.4 Over the last two decades, studies have
`shown an association between aortic valve calcification and
`traditional risk factors for atherosclerotic cardiovascular dis-
`ease, including age, male gender, smoking, hypertension, low-
`density lipoprotein cholesterol (LDL-C) levels, and diabetes
`mellitus.2,7 Furthermore, the apolipoprotein E allele, apoE4,
`which has been shown to be associated with an increased risk
`for coronary heart disease, is also associated with the devel-
`opment of AS.8 In addition, there is evidence that certain
`polymorphisms in the lipoprotein(a) gene may play a causal
`role in calcification and stenosis of the aortic valve.9 Several
`studies have also suggested a role for nitric oxide resistance
`and reactive oxygen species.10–12 However, three prospec-
`tive, randomized, controlled studies have shown the failure
`of lipid-lowering therapy to halt or slow the progression of
`AS and associated outcomes, and a retrospective case–control
`study suggested that high-dose atorvastatin did not prevent
`the development of calcific AS.13–16 Thus, there is growing
`evidence that atherosclerosis and AS, although sharing some
`pathophysiological features, have important differences in
`pathogenesis with considerable implications for treatment.
`Therefore, a broad search for the causative factors in AS
`is underway. The mechanisms of progressive aortic valve cal-
`cification are an appealing target, because elucidation of these
`would likely provide targets for treatments aimed at preventing
`the progression of AS or even reversing the process. There is
`some evidence that valve interstitial cells and valve endothelial
`cells can be transformed into osteoblast-like cells and thereafter
`likely contribute to ongoing valvular calcification.3,5 Further-
`more, mutations in NOTCH1, a signaling protein involved
`in regulation of osteoblasts, have been proposed to result in a
`bicuspid aortic valve and calcific AS.17 Finally, broad genomic
`screens18 and more focused genetic studies19–21 offer another
`angle of attack to determine the critical pathways by which
`normal aortic valves progress to severe AS.
`Congenital abnormalities of the aortic valve frequently
`predispose to AS. A bicuspid aortic valve is the most common
`
`Page 02 of 10
`
`

`

`congenital abnormality associated with AS and is found in
`1–2% of the general population.22 One single-center study of
`932 consecutive patients who underwent aortic valve replace-
`ment for AS without mitral stenosis (thus excluding most
`rheumatic disease) found definite congenital abnormalities in
`54% of the aortic valves, with 5% being unicuspid valves and
`the remainder bicuspid.23 In the same study, the average age
`of valve replacement in those with a bicuspid valve was 67 ± 11
`years, compared with 51 ± 14 years in those with unicuspid
`valves and 74 ± 8 years in those with tricuspid valves.23 How-
`ever, the exact prevalence of congenital aortic valve abnormal-
`ities in patients undergoing aortic valve replacement for AS
`varies depending on the inclusion criteria.24–26 Importantly,
`a bicuspid valve can be associated with coarctation of the
`aorta, ascending aortic aneurysm, aortic dissection, infective
`endocarditis, Turner’s syndrome (the absence of one X chro-
`mosome), a ventricular septal defect, and Shone’s syndrome
`(supra-valvular mitral ring, parachute mitral valve, subaortic
`stenosis, and aortic coarctation).22,27
`Rheumatic heart disease is rare in the United States but
`remains an important cause of AS in developing countries.
`Rheumatic AS is characterized by fusion of the valve commis-
`sures because of an inflammatory response, which predisposes
`to further valvular injury and eventually results in valve fibro-
`sis and calcification. Furthermore, rheumatic AS is almost
`always seen in conjunction with rheumatic mitral stenosis as
`the mitral valve is more frequently affected by rheumatic heart
`disease than the aortic valve.
`Regardless of the etiology, valvular AS results in a fixed
`obstruction to left ventricular outflow. By Ohm’s law (V = IR),
`as the resistance to flow (R) increases with decreasing valve
`area, the driving pressure (V) must increase to maintain the
`same flow (I or cardiac output) across the aortic valve. Laplace’s
`law states σ = (Pr)/(2t), where σ is the left ventricular wall
`stress, P is transmural pressure (which is approximated by the
`left ventricular intracavitary pressure), r is the left ventricular
`radius, and t is the left ventricular wall thickness. Therefore,
`as left ventricular pressure rises to maintain cardiac output in
`the face of outflow obstruction, left ventricular wall thickness
`increases to minimize the change in wall stress. Over time, as
`the valve area progressively decreases, this process results in
`the development of left ventricular hypertrophy. While ini-
`tially an adaptive response, left ventricular hypertrophy even-
`tually results in myocyte disarray and dysregulation, which
`can lead in turn to failure of the contractile function of the
`left ventricle. Clinically, this is apparent as the onset of heart
`failure symptoms and is a late clinical finding in severe AS.
`clinical Manifestations
`The three classic symptoms of AS are exertional angina, syn-
`cope, and heart failure.28 However, symptoms are frequently
`insidious at the onset and can be highly variable among
`patients with similar degrees of valve stenosis. Many patients
`note a subtle decrease in exercise tolerance as the first symptom
`
`Valvular aortic stenosis
`
`of AS. Furthermore, AS tends to be quite advanced by the
`time it results in clinical symptoms. In the original report
`by Ross and Braunwald, the mean survival after the onset of
`angina, syncope, and heart failure was five, three, and two
`years, respectively.
`Angina results from an imbalance in myocardial oxygen
`supply and demand. Angina in the setting of aortic valve
`stenosis may be secondary to the development of concomitant
`coronary artery disease but may also occur in the absence of
`fixed atherosclerotic disease. Increased myocardial oxygen
`demand is a result of hypertrophy of the left ventricle and the
`increased afterload conferred by the fixed obstruction to left
`ventricular outflow. Decreased myocardial oxygen supply is a
`result of both reduced mean arterial pressure and decreased
`coronary blood flow. As the severity of valvular obstruction
`increases, the systolic ejection period is lengthened, which
`necessarily results in a decrease in the time spent in diastole
`at a given heart rate. As coronary perfusion occurs primarily
`during diastole, coronary blood flow decreases. In addition,
`mean arterial pressure declines as a result of fixed obstruction
`to left ventricular outflow, which further decreases coronary
`blood flow. Therefore, increased myocardial oxygen demand
`and decreased myocardial oxygen supply result in character-
`istic angina.
`Syncope is a consequence of the inability of the heart to
`increase cardiac output to meet the demands of the body. This
`can be evident as an exaggerated orthostasis, whereby chang-
`ing from a sitting to a standing position results in venous pool-
`ing of blood, which decreases preload and therefore decreases
`cardiac output. Normally, heart rate and contractility increase
`to raise cardiac output and thereby maintain cerebral perfusion
`until contraction of the venous compartment, and thus resto-
`ration of preload, can occur. However, in the setting of sig-
`nificant AS, the fixed outflow obstruction limits the increase
`in cardiac output, which can result in cerebral hypoperfusion
`and syncope. Similarly, AS can cause syncope during exertion,
`as the outflow obstruction limits the increase in cardiac output
`that is required to compensate for the vasodilation and higher
`blood flow to exercising skeletal muscle.
`Heart failure is a late manifestation of AS and is associ-
`ated with a poor prognosis. As valvular obstruction worsens,
`the compensatory left ventricular hypertrophy that develops to
`normalize wall stress also results in a less compliant ventricle
`and therefore increases left ventricular end-diastolic pressure.
`This increased pressure is transmitted to the left atrium, the
`pulmonary vasculature, and eventually the right side of the
`heart, and these elevated pressures are clinically manifested as
`exertional dyspnea. In addition, progressive hypertrophy and
`severe obstruction to left ventricular outflow can lead to left
`ventricular systolic dysfunction. Therefore, symptoms of heart
`failure because of AS may be left-sided, including rest or exer-
`tional dyspnea, orthopnea, and paroxysmal nocturnal dyspnea,
`or right-sided, including anorexia, abdominal swelling, and
`peripheral edema.
`
`CliniCal MediCine insights: Cardiology 2014:8(s1)
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`

`Czarny and Resar
`
`clinical Assessment
`The diagnosis of AS begins with a physical examination. The
`classic murmur is a crescendo–decrescendo murmur heard
`best at the right upper sternal border, with a peak that shifts
`later in systole as the severity of AS increases. This murmur
`can be differentiated from that of a dynamic outflow tract
`obstruction (eg, hypertrophic obstructive cardiomyopathy) in
`that the murmur of AS will soften with Valsalva as the flow
`across the valve decreases, whereas the murmur of a dynamic
`outflow tract obstruction will increase as preload decreases.
`A soft or absent aortic component of the second heart sound
`(A2) may also be appreciated and is a marker of severity. Fur-
`thermore, there may be a delayed and blunted carotid upstroke
`(pulsus parvus et tardus) that can be appreciated by auscultation
`of the heart with simultaneous carotid palpation, though this
`finding may be more difficult to appreciate in elderly patients
`with a non-compliant arterial tree. Similarly, simultaneous
`palpation of the ipsilateral brachial and radial pulses may
`disclose a notable delay in systolic pulsation from brachial to
`radial artery. As AS severity increases, the findings of sys-
`tolic heart failure may become more prominent, including an
`S3 or S4 gallop, the irregular rhythm of atrial fibrillation, an
`enlarged and laterally displaced point of maximal impulse,
`pulmonary rales, jugular venous distention, hepatomegaly,
`ascites, and peripheral edema.
`After the physical examination, the next step in the eval-
`uation of AS is a transthoracic echocardiogram. This imaging
`modality can confirm the diagnosis of AS, help to determine
`the severity of valvular obstruction, exclude alternative diagno-
`ses, provide information on the etiology, and assess comorbid
`conditions, including aortic root pathology and aortic insuffi-
`ciency. Echocardiographic imaging of the stenotic aortic valve
`almost always shows thickening and calcification of the aor-
`tic valve, though this is not specific for any one etiology and
`rather is more frequently the final common pathologic result.
`Imaging may show a congenital bicuspid aortic valve or fusion
`of the commissures to suggest rheumatic AS. A mitral valve
`with the characteristic “hockey-stick” appearance of rheu-
`matic mitral stenosis combined with AS suggests combined
`aortic and mitral valve disease as a long-term consequence of
`rheumatic fever. Echocardiographic assessment of the aortic
`valve is also important to determine the degree of associated
`aortic regurgitation, which may complicate management.
`Furthermore, imaging of the aortic root and ascending aorta
`may reveal aortic dilatation as may be seen in conjunction with
`a congenital bicuspid valve.
`The severity of AS is typically initially assessed by
`echocardiographic features.29,30 Complete interrogation of the
`aortic valve includes assessment of the maximum transvalvu-
`lar velocity, determination of the mean transvalvular pressure
`gradient, calculation of the aortic valve area by the continuity
`equation (ALVOTVLVOT = AAVVAV or ALVOTVTILVOT = AAV
`VTIAV, where A is the area, V is the peak velocity, VTI is the
`velocity–time integral, LVOT is the left ventricular outflow
`
`18
`
`CliniCal MediCine insights: Cardiology 2014:8(s1)
`
`tract, and AV is the aortic valve), measurement of the aortic
`valve area by planimetry, and calculation of the dimension-
`less index (VLVOT/VAV or VTILVOT/VTIAV). Both the standard
`two-dimensional echocardiogram probe as well as the Pedoff
`probe should be used, and the highest gradients or velocities
`obtained are used in the calculations. For patients in irregular
`rhythms such as atrial fibrillation, measurements should be
`averaged over four or five consecutive beats. The findings are
`then classified as in Table 1.
`When non-invasive assessment of the aortic valve is
`inconclusive in a symptomatic patient or there is a discrep-
`ancy between symptoms and the severity of findings by
`non-invasive studies, the gold standard is left and right heart
`catheterization.30 A right heart catheterization is performed
`with a balloon-tipped Swan-Ganz catheter, and cardiac output
`is determined by either thermodilution or the Fick equation.
`Left heart catheterization is then performed, usually by retro-
`grade catheterization of the left ventricle. The aortic transval-
`vular gradient is assessed by simultaneous measurement of left
`ventricular and ascending aortic pressures, either with a single
`dual-lumen catheter or with two separate catheters. The mean
`aortic transvalvular gradient is determined and averaged over
`several beats, and the aortic valve area is calculated by the
`Gorlin equation31:
`
`
`
`where AVA is the aortic valve area in cm2, CO is the
`cardiac output in L/minute, C is a constant, SEP is the systolic
`ejection period in seconds/minute, LVsm is the LV mean sys-
`tolic ejection pressure in mmHg, and Asm is the mean aortic
`systolic ejection pressure in mmHg. The results are classified
`in Table 1.
`The single largest confounder of the assessment of AS is
`concomitant heart failure, which can lead to lower aortic valve
`velocities and gradients despite severe or critical valvular AS
`and therefore underestimation of the severity of AS. Suspi-
`cion for this “low-flow, low-gradient” (LF–LG) severe AS is
`raised when an echocardiogram shows a calcified aortic valve
`with reduced opening, a calculated aortic valve area #1.0 cm2
`(or #0.6 cm2/m2), a mean gradient ,40 mmHg or a peak
`velocity ,4.0 m/s, and a left ventricular ejection fraction
`(LVEF) ,50%.30 In this setting, the question is whether
`the poor contractile function is a consequence of severe AS,
`in which case valve replacement is indicated, or if the low
`gradients and reduced valve area are a consequence of a low-
`flow state because of other myocardial disease (eg, coronary
`artery disease, idiopathic cardiomyopathy) in the absence of
`severe AS, in which case valve replacement is contraindicated.
`A low-dose dobutamine stress test (2.5–20 mcg/kg/minute),
`which is done either in the echocardiography laboratory or in
`the catheterization laboratory, can be helpful to differentiate
`between LF–LG severe AS and pseudo-severe AS (Class IIa,
`
`AVA
`
`=
`
`CO
`)
`(
`SEP LVsm
`
`44 5. C
`
`−
`
`A
`
`sm
`
`Page 04 of 10
`
`

`

`Level of Evidence B).30,32 Patients with LF–LG severe AS
`will generally have a mean gradient of $40 mmHg, a final
`aortic valve area of ,1.0 cm2, and an increase in aortic valve
`area of #0.3 cm2 with dobutamine stress, whereas those with
`pseudo-severe stenosis will have an increase in aortic valve
`area and LVEF with indices of AS failing to meet criteria for
`severe stenosis.29 Furthermore, in those patients with LF–LG
`severe AS, an increase in LVEF or LV stroke volume of #20%
`with dobutamine stress is termed “no flow reserve” or “no con-
`tractile reserve.” Such patients have a higher prevalence of
`concomitant coronary artery disease and a worse prognosis
`than those with flow reserve.33
`Recently, the phenomenon of LF–LG valvular AS with
`a preserved LVEF (“paradoxical” LF–LG AS) has been rec-
`ognized. In this case, “low-flow” is defined by a stroke volume
`indexed to body surface area of #35 mL/m2.33 Such patients
`have a smaller LV cavity size and a greater LV relative wall
`thickness with reduced myocardial contractility. They are
`more frequently female, older, and have less compliant arte-
`rial trees. Furthermore, they have worse survival than simi-
`lar patients with a preserved LVEF and normal flow.34,35 The
`“paradoxical” LF–LG setting likely represents an advanced
`stage of cardiomyopathy and aortic valve disease, and the
`“paradoxical” nature is likely a consequence of the finding that
`the LVEF does not necessarily correlate with myocardial con-
`tractile function in thickened, small hearts.33
`Several other comorbidities may confound the assess-
`ment of AS.29 Uncontrolled systemic hypertension may alter
`the LVEF and aortic transvalvular flow; hence, hyperten-
`sion should be well controlled during the diagnostic study.
`Concomitant aortic insufficiency is present in about 80% of
`patients with AS and can lead to higher than expected gradi-
`ents across the valve because of increased transvalvular flow.
`In addition, other high-output states (severe anemia, arterio-
`venous fistula, hemodialysis, and hyperthyroidism) will also
`increase the flow across the aortic valve and thereby confound
`measurements of stenosis severity. Finally, underestimation of
`transvalvular gradients frequently occurs when the ultrasound
`probe is not parallel to the direction of flow, and can lead to
`underestimation of the severity of AS.
`Management
`Medical therapy. Once established, the rate of pro-
`gression of AS varies considerably from one patient to the
`next and is unpredictable.36 However, it is clear that the
`vast majority of adverse cardiac events occur in symptom-
`atic patients; hence, the general strategy is one of watchful
`waiting with serial echocardiograms and clinical visits to
`assess the development of symptoms related to AS. There-
`fore, the American Heart Association (AHA) and American
`College of Cardiology (ACC) guidelines recommend that
`asymptomatic patients with mild, moderate, and severe AS
`have a transthoracic echocardiogram every 3–5 years, every
`1–2 years, and every 6–12 months, respectively. Furthermore,
`
`Valvular aortic stenosis
`
`a repeat echocardiogram is indicated if there is a change in
`symptoms or physical examination to suggest worsening of
`stenosis. In addition, exercise stress testing can be performed
`in the asymptomatic patient with severe AS when the history
`is unclear to assess exercise-induced symptoms or an abnormal
`blood pressure response, though is absolutely contraindicated
`in those with symptomatic severe AS.30
`Severe AS is primarily a mechanical problem (ie, a fixed
`obstruction to flow), and therefore, definitive management is
`directed at relief of the obstruction by surgical or transcath-
`eter therapies. Medically managed symptomatic AS has an
`extremely poor prognosis, with a 5-year mortality of 50–60%
`and a 10-year mortality approaching 90%.37,38 There are no
`medical therapies that can slow the progression of AS. Despite
`the purported role of atherogenesis in the development and
`progression of calcific AS, statin therapy has not been shown
`to slow or halt worsening of valvular AS.13,14 However, patients
`with mild or moderate AS and a depressed LVEF should be
`treated with standard evidence-based heart failure therapies,
`which may include angiotensin-converting enzyme (ACE)
`inhibitors, angiotensin receptor blockers (ARBs), beta-blockers,
`and aldosterone receptor antagonists. In addition, patients
`with mild or moderate AS should have their comorbid condi-
`tions, including hypertension, managed appropriately.30
`Owing to the inefficacy of medical therapy in AS, the
`non-operative management of severe AS is directed at opti-
`mizing comorbidities while avoiding medications that will
`adversely alter hemodynamics. Medications that reduce pre-
`load, including nitroglycerin, and that decrease afterload,
`including ACE inhibitors, ARBs, hydralazine, and non-selec-
`tive beta-blockers, are contraindicated in severe AS. As the
`severely stenotic aortic valve limits the compensatory increase
`in cardiac output, use of these medications can lead to a down-
`ward hemodynamic spiral in which decreased preload or after-
`load results in reduced mean arterial pressure that worsens
`coronary perfusion. This in turn leads to myocardial ischemia,
`which results in a decreased cardiac output and therefore
`a further reduction in mean arterial pressure. Once this spiral
`is initiated, it can be difficult or impossible to restore the
`delicate hemodynamic balance, and significant adverse events
`including death may occur.
`Despite this classic teaching, there may be select groups
`of patients for whom medical therapy can offer some benefit.
`A recent study prospectively evaluated the effects of sodium
`nitroprusside on 18 consecutive, symptomatic, LF–LG severe AS
`patients with hypertension and a preserved LVEF (mean aortic
`transvalvular pressure ,40 mmHg, aortic valve area ,1.0 cm2,
`LVEF .50%, and aortic systolic pressure .140 mmHg) during
`left and right heart catheterization.39 Nitroprusside infusion
`decreased aortic, LV end-diastolic, and pulmonary artery
`pressures, and led to a statistically significant increase in the
`mean aortic transvalvular gradient (27 ± 5 to 29 ± 6 mmHg,
`P = 0.02) and an increase in the aortic valve area (0.86 ± 0.11 to
`1.02 ± 0.16 cm2, P = 0.001). The authors theorized that these
`
`CliniCal MediCine insights: Cardiology 2014:8(s1)
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`Page 05 of 10
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`Czarny and Resar
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`patients have serial obstructions to forward flow encompassing
`both the aortic valve and systemic arterial tree, and that
`treating the systemic hypertension allows better hemodynamic
`compensation for the aortic valve stenosis. Therefore, there
`may be a role for gentle titration of afterload reduction while
`in a monitored setting to achieve blood pressure control in
`hypertensive patients with LF–LG AS with a preserved LVEF
`(“paradoxical” LF–LG AS).
`In addition, there may be a benefit of intravenous vaso-
`dilators in the management of severe AS leading to acute
`decompensated heart failure (ADHF). Khot et al evalu-
`ated the effects of sodium nitroprusside infusion,40 a potent
`arterial vasodilator and a common therapy for ADHF in
`patients without severe AS, in patients in the intensive care
`unit with a depressed LVEF (#35%), severe AS (aortic valve
`area #1.0 cm2), and a decreased cardiac index (#2.2 L/
`minute/m2) without hypotension
`(mean arterial pres-
`sure ,60 mmHg) or a need for intravenous inotropes or vaso-
`pressor support. It is well known that relieving the profound
`vasoconstriction characteristic of ADHF with arterial vasodi-
`lators results in improved forward flow and improved systemic
`hemodynamics, but fears relating to the inability of the heart
`with severe AS to augment cardiac output to compensate for
`a decrease in afterload led to this therapy being avoided when
`severe AS was comorbid. However, Khot et al showed that
`intravenous nitroprusside resulted in significant improve-
`ments in cardiac index (baseline 1.60 ± 0.35 L/minute/m2)
`in 6 hours (2.22 ± 0.44 L/minute/m2, P , 0.001) and in
`24 hours (2.52 ± 0.55 L/minute/m2, P , 0.001 for compari-
`son with baseline), and that both mean and peak gradients
`(37 ± 20 mmHg and 64 ± 37 mmHg, respectively) increased in
`24 hours (60 ± 30 mmHg and 100 ± 53 mmHg, respectively;
`P = 0.03 for both comparisons) though the aortic valve area
`remained unchanged (0.6 ± 0.1 cm2 at baseline and 24 hours).
`Furthermore, this effect was seen in those with both low-
`gradient and high-gradient severe AS and was generally well
`tolerated. Therefore, intravenous vasodilator therapy may be
`useful for managing ADHF in patients with severe AS as a
`bridge to definitive therapy while in an intensive care setting.
`surgical and transcatheter therapies. The most simple
`but least effective