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Electron Beam Computed Tomography: The Latest “Stethoscope” for Calcific Aortic Valve Disease

  • Gian M. Novaro
    Correspondence
    Address reprint requests and correspondence to Gian M. Novaro, MD, MS, Department of Cardiology, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL 33331
    Affiliations
    Department of Cardiology, Cleveland Clinic Florida, Weston
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      Calcific aortic valve disease (CAVD), namely valvular aortic sclerosis and stenosis, is common in a growing elderly population, with calcific aortic stenosis being one of the most common indications for valve replacement. Once considered the result of aging and passive hemodynamic “wear and tear,” so-called senile-type aortic stenosis, CAVD is now known to result from an active disease process with an atheromatous, inflammatory, and osteocalcific biology.
      • Otto CM
      • Kuusisto J
      • Reichenbach DD
      • Gown AM
      • O'Brien KD
      Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis: histological and immunohistochemical studies.
      • O'Brien KD
      • Reichenbach DD
      • Marcovina SM
      • Kuusisto J
      • Alpers CE
      • Otto CM
      Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of ‘degenerative’ valvular aortic stenosis.
      • Mohler III, ER
      • Gannon F
      • Reynolds C
      • Zimmerman R
      • Keane MG
      • Kaplan FS
      Bone formation and inflammation in cardiac valves.
      The epidemiology of CAVD is linked to various atherosclerotic risk factors, including increased low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) levels, hypertension, and diabetes.
      • Stewart BF
      • Siscovick D
      • Lind BK
      • et al.
      Clinical factors associated with calcific aortic valve disease: Cardiovascular Health Study.
      Histological studies show a well-regulated cellular process occurring in the subendothelium of the aortic side of the aortic valve leaflets, characterized by oxidized lipid and lipoprotein deposition, macrophage and T-lymphocyte infiltration, and microscopic calcification
      • Otto CM
      • Kuusisto J
      • Reichenbach DD
      • Gown AM
      • O'Brien KD
      Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis: histological and immunohistochemical studies.
      • O'Brien KD
      • Reichenbach DD
      • Marcovina SM
      • Kuusisto J
      • Alpers CE
      • Otto CM
      Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of ‘degenerative’ valvular aortic stenosis.
      ; calcification is colocalized to areas of lipoprotein accumulation.
      • O'Brien KD
      • Reichenbach DD
      • Marcovina SM
      • Kuusisto J
      • Alpers CE
      • Otto CM
      Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of ‘degenerative’ valvular aortic stenosis.
      As the disease process advances, calcification predominates,
      • Mohler III, ER
      • Gannon F
      • Reynolds C
      • Zimmerman R
      • Keane MG
      • Kaplan FS
      Bone formation and inflammation in cardiac valves.
      leading to increased leaflet stiffness and eventual obstructive valvular disease. In elderly patients, aortic valve calcification (AVC) is associated with increased cardiovascular mortality.
      • Otto CM
      • Lind BK
      • Kitzman DW
      • Gersh BJ
      • Siscovick DS
      Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly.
      The degree of AVC is a strong predictor of both disease progression
      • Bahler RC
      • Desser DR
      • Finkelhor RS
      • Brener SJ
      • Youssefi M
      Factors leading to progression of valvular aortic stenosis.
      and outcome of aortic stenosis.
      • Rosenhek R
      • Binder T
      • Porenta G
      • et al.
      Predictors of outcome in severe, asymptomatic aortic stenosis.
      Recent data suggest that higher AVC burden in patients with aortic stenosis is associated with lower event-free survival, independent of clinical and echocardiographic predictors.
      • Messika-Zeitoun D
      • Aubry MC
      • Detaint D
      • et al.
      Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography.
      Thus, the ability to accurately and quantitatively measure AVC, a marker of disease activity and outcome, would be highly desirable.
      Up to now, CAVD has been detected by auscultation, radiographic and fluoroscopic evaluation, and echocardiography. Electron beam computed tomography (EBCT) represents the latest modality in the armamentarium of CAVD evaluation, facilitating noninvasive detection and quantification of AVC.
      • Messika-Zeitoun D
      • Aubry MC
      • Detaint D
      • et al.
      Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography.
      • Budoff MJ
      • Mao S
      • Takasu J
      • Shavelle DM
      • Zhao XQ
      • O'Brien KD
      Reproducibility of electron-beam CT measures of aortic valve calcification.
      • Pohle K
      • Mäffert R
      • Ropers D
      • et al.
      Progression of aortic valve calcification: association with coronary atherosclerotic and cardiovascular risk factors.
      As an imaging modality with a relatively novel use, accuracy and reproducibility of EBCT need to be proved. Using either Agatston scoring or volumetric methods for quantifying AVC, studies have confirmed low interscan (6.2%-7.0%), interobserver (5.1%), and intraobserver (1.0%) variability.
      • Budoff MJ
      • Mao S
      • Takasu J
      • Shavelle DM
      • Zhao XQ
      • O'Brien KD
      Reproducibility of electron-beam CT measures of aortic valve calcification.
      Similar to the well-validated quantification of coronary calcification by EBCT, determination of AVC burden by EBCT accurately estimates valvular calcium mass compared to pathologic examination.
      • Messika-Zeitoun D
      • Aubry MC
      • Detaint D
      • et al.
      Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography.
      The ability of EBCT to provide diagnostic information and grading of the severity of aortic stenosis,
      • Messika-Zeitoun D
      • Aubry MC
      • Detaint D
      • et al.
      Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography.
      as well as to determine AVC progression,
      • Pohle K
      • Mäffert R
      • Ropers D
      • et al.
      Progression of aortic valve calcification: association with coronary atherosclerotic and cardiovascular risk factors.
      establishes it as a useful and complementary tool for assessing CAVD. In 100 patients, investigators showed a strong association between AVC scores measured by EBCT and severity of aortic stenosis determined by echocardiography.
      • Messika-Zeitoun D
      • Aubry MC
      • Detaint D
      • et al.
      Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography.
      An AVC score of 1100 Agatston units detected severe aortic stenosis (valve area <1 cm) with a sensitivity of 93% and a specificity of 82%.
      Studies of the association between aortic stenosis and cardiovascular risk factors have thus far been conducted predominantly by using echocardiographic assessment of CAVD.
      • Stewart BF
      • Siscovick D
      • Lind BK
      • et al.
      Clinical factors associated with calcific aortic valve disease: Cardiovascular Health Study.
      Semiquantitative scoring systems, derived from echocardiographic 2-dimensional imaging, have been used for grading AVC. In this issue of the Mayo Clinic Proceedings, Pohle et al
      • Pohle K
      • Otte M
      • Mäffert R
      • et al.
      Association of cardiovascular risk factors to aortic valve calcification as quantified by electron beam computed tomography.
      report the association among traditional cardiovascular risk factors, coronary calcification, and AVC as quantified by EBCT. The study population consisted of 1000 consecutive patients referred for detection of coronary calcification. At baseline, the prevalence of cardiovascular risk factors was high, and coronary calcification was common (in 83% of the study group). Patients with renal disease were excluded because of high rates of dystrophic calcification. In this middle-aged referral population, AVC was present in 18% of patients, and its prevalence and burden were greater in patients with coronary calcification, hyperlipidemia, hypertension, or diabetes vs those without these conditions. The prevalence of AVC was 34% in patients with 4 or 5 of the cardiovascular risk factors. In multivariable logistic regression analysis, hyperlipidemia and coronary calcification were significant predictors of AVC.
      Several findings in this study are important and merit further comment. The study links both the presence and the extent of AVC to hyperlipidemia, confirming earlier observations that showed a close association between hyperlipidemia and CAVD. To my knowledge, the study by Pohle et al is the first to elegantly do so using AVC detected by EBCT. Prior evidence supports an association between AVC and coronary artery disease. In clinical cohorts with severe aortic stenosis, up to 50% of patients have significant coronary artery disease by angiography.
      • Rapp AH
      • Hillis LD
      • Lange RA
      • Cigarroa JE
      Prevalence of coronary artery disease in patients with aortic stenosis with and without angina pectoris.
      These findings may underrepresent the atherosclerotic burden because angiography can limit quantification of disease compared to other imaging modalities. Pohle et al found that an overwhelming majority of patients (96%) with AVC had coronary calcification, a finding possibly related to referral bias in their high-risk population. Nonetheless, this observation provides valuable insight into the clinical importance of AVC, showing that a high prevalence of coexisting occult coronary atherosclerotic disease may explain why AVC is an independent predictor of adverse cardiovascular outcome.
      • Otto CM
      • Lind BK
      • Kitzman DW
      • Gersh BJ
      • Siscovick DS
      Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly.
      Despite the association between coronary disease and CAVD, it is notable that these disease processes do not always coexist. Most patients with coronary disease do not have aortic stenosis. Conversely, in the study by Pohle et al, AVC occurred in 3.8% of patients with no coronary calcification. Furthermore, the reason why only a minority of patients with aortic sclerosis will have progression to aortic stenosis, conditions thought to be a continuum of the same disease, is unclear. These disparities suggest that the development of advanced CAVD, namely aortic stenosis, is influenced by factors yet unidentified. Because aortic stenosis is a multifactorial condition, emphasis should also be placed on identifying potential alternative, nonatherosclerotic risk factors. Accordingly, a genetic underpinning for the development of aortic stenosis has been suggested. Two genetic markers have been purported to be linked to aortic stenosis, the vitamin D receptor polymorphism
      • Ortlepp JR
      • Hoffmann R
      • Ohme F
      • Lauscher J
      • Bleckmann F
      • Hanrath P
      The vitamin D receptor genotype predisposes to the development of calcific aortic valve stenosis.
      and the ApoE4 allele.
      • Novaro GM
      • Sachar R
      • Pearce GL
      • Sprecher DL
      • Griffin BP
      Association between apolipoprotein E alleles and calcific valvular heart disease.
      Osteoporosis and arterial calcification coexist frequently, independent of age. Similarly, osteoporosis has been linked to CAVD in several studies.
      • Stewart BF
      • Siscovick D
      • Lind BK
      • et al.
      Clinical factors associated with calcific aortic valve disease: Cardiovascular Health Study.
      The osteoporosis candidate gene, the vitamin D receptor polymorphism, represents a biologically plausible link because it is associated with more rapid bone loss and lower bone mineral density. However, its association with CAVD needs to be confirmed in further studies. Race may also influence the risk of developing AVC. Both by EBCT and pathologic studies, black people appear to have less arterial calcification than do white people. Interestingly, racial differences exist in regard to osteoporosis. The incidence in black women is half that in white women, and black women have lower indices of bone turnover compared with white women. These observations lend support for future research in CAVD to help understand the observed racial phenotypic discrepancy in the development of dystrophic calcification and the role of genetic factors associated with calcium and lipoprotein metabolism.
      The current findings by Pohle et al
      • Pohle K
      • Otte M
      • Mäffert R
      • et al.
      Association of cardiovascular risk factors to aortic valve calcification as quantified by electron beam computed tomography.
      are important and reconfirm the strong link between hyperlipidemia and AVC. In a prior study by Pohle et al,
      • Pohle K
      • Mäffert R
      • Ropers D
      • et al.
      Progression of aortic valve calcification: association with coronary atherosclerotic and cardiovascular risk factors.
      AVC progressed more rapidly, as assessed by EBCT, in patients with LDL-C levels greater than 130 mg/dL compared with patients whose levels were lower than 130 mg/dL. As mentioned previously, increased AVC is associated with more rapid aortic stenosis progression and worse outcome. Evidence from animal models of AVC support the notion that hyperlipidemia plays a role in the development of AVC. In experimental hypercholesterolemia, an atheromatous, bonelike phenotype can be demonstrated on aortic leaflets.
      • Rajamannan NM
      • Subramaniam M
      • Springett M
      • et al.
      Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve.
      Hence, clinical and experimental data suggest that lowering lipid levels might slow the progression of AVC.
      Retrospective clinical studies suggest that treatment with statin drugs slows the rate of CAVD progression, as assessed by echocardiography
      • Bellamy MF
      • Pellikka PA
      • Klarich KW
      • Tajik AJ
      • Enriquez-Sarano M
      Association of cholesterol levels, hydroxymethylglutaryl coenzyme-A reductase treatment, and progression of aortic stenosis in the community.
      or EBCT.
      • Shavelle DM
      • Takasu J
      • Budoff MJ
      • Mao S
      • Zhao XQ
      • O'Brien KD
      HMG CoA reductase inhibitor (statin) and aortic valve calcium.
      Furthermore, in experimental AVC, statins led to a reduction in both lipid and bone-matrix deposition.
      • Rajamannan NM
      • Subramaniam M
      • Springett M
      • et al.
      Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve.
      The striking data from the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial showed that intensive lipid-lowering treatment can stop generalized atherosclerotic disease progression.
      • Nissen SE
      • Tuzcu EM
      • Schoenhagen P
      • REVERSAL Investigators
      • et al.
      Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.
      Whether similar results in AVC and CAVD can be achieved with intensive lipid lowering is currently being examined in prospective clinical trials.
      The use of AVC as a clinical trial end point in the study of CAVD deserves comment. Statin trials in CAVD that use aortic stenosis–related events and the need for aortic valve replacement as end points will require large numbers of patients followed up for several years. The use of AVC volume as a surrogate end point should now be accepted as valid on the basis of its demonstrated importance as an independent predictor of adverse outcomes.
      • Messika-Zeitoun D
      • Aubry MC
      • Detaint D
      • et al.
      Evaluation and clinical implications of aortic valve calcification measured by electron-beam computed tomography.
      With EBCT quantification of AVC, effects of a medical intervention can be detected earlier in the course of disease progression and with more sensitivity and statistical power.
      In 1816, a young French physician named Rene Theophile Hyacinthe Laennec discovered and named the stethoscope. The word stethoscope comes from the Greek terms stethos, meaning chest, and scope, meaning to see. For the past 20 years, echocardiography has been the modality of choice for visual assessment of CAVD and remains the preferred imaging tool for its hemodynamic evaluation. With several complementary studies showing its accuracy, reproducibility, and more recently its diagnostic and prognostic potential, EBCT provides the most recent “stethoscope” in evaluating CAVD, allowing us “to see” with high sensitivity the morphologic marker of lesion severity and activity—AVC. The emerging role of EBCT in detecting AVC in CAVD will likely be as follows: (1) to provide supportive information on severity of stenosis in patients with conflicting or incomplete hemodynamic data; (2) to serve as an alternative, more sensitive technique in the study of risk factors for the development and progression of CAVD; and (3) perhaps more importantly, to provide an accurate surrogate end point for detection of lesion progression or regression in therapeutic pharmacological trials, similar to the use of intravascular ultrasonography in coronary artery disease.

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