Association Between Aortic Valve Calcification and Myocardial Ischemia, Especially in Asymptomatic Patients

Study Population and Clinical Characteristics

Between April 2008 and March 2011, 1,153 consecutive patients underwent both adenosine stress ²⁰¹Tl MPS and echocardiography at Hiroshima University Hospital, Japan. We excluded patients with prosthetic aortic valves, bicuspid valves, or aortic valve stenosis (n = 59).We also excluded patients with prior myocardial infarction or coronary revascularization therapy (n = 386) and patients undergoing hemodialysis (n = 39). Finally, 669 patients were included in this study (Fig. 1).

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FIGURE 1.

Patient disposition and results of MPS. Numbers of asymptomatic patients are also shown.

At the time of the MPS test, all patients provided information on their demographic characteristics, medical history, medication use, and symptoms (including whether they had no symptoms). In 311 asymptomatic patients, the main reasons for the MPS test, other than having arteriosclerotic risk factors, included having an abnormal resting electrocardiogram (n = 152), having inconclusive results of other modalities to detect CAD (n = 121), and being scheduled for high-risk surgery (n = 38). We assessed the presence or absence of hypertension, diabetes mellitus, dyslipidemia, hyperuricemia, chronic kidney disease, and current smoking, because these are established risk factors for the presence of AVC (1–4,6–10). Hypertension was defined as either systolic or diastolic blood pressure ≥ 140/90 mm Hg or current antihypertensive therapy. We defined diabetes mellitus as HbA1c ≥ 6.5% (21) or current use of hypoglycemic agents. Dyslipidemia was defined as total cholesterol ≥ 220 mg/dL, low-density lipoprotein cholesterol ≥ 140 mg/dL, high-density lipoprotein cholesterol < 40 mg/dL, or current treatment with lipid-lowering medication. Hyperuricemia was defined as serum uric acid ≥ 7.0 mg/dL or current antihyperuricemic therapy. Chronic kidney disease was defined as estimated glomerular filtration rate < 60 mL/min. Patients were considered current smokers if they had smoked at least one cigarette per day within the previous month. We also evaluated the results of coronary angiography performed within 3 mo of the MPS test. Obstructive CAD was defined as >50% stenosis in the epicardial coronary arteries.

Echocardiographic Images

Echocardiography was performed using commercially available systems (iE33Vision [Philips Electronics N.V.], ARTIDA [Toshiba Medical Systems Co.], or Vivid7 Dimension [GE Healthcare U.K. Ltd.]). Echocardiographic data were recorded on a digital recording system (Prime VITA; Nihon-koden) and were interpreted by cardiologists who were unaware of the MPS findings.

Two-dimensional assessment of AVC was performed from the parasternal long-axis, short-axis, and apical long-axis views, with appropriate gain settings. Peak antegrade flow across the aortic valve was measured from apical views by continuous-wave Doppler. Aortic valve stenosis was defined as thickened leaflets with a reduced systolic opening on a 2-dimensional echocardiogram and increased antegrade velocity (≥2.5 m/s on continuous-wave Doppler). Using previously reported criteria (1,4), we defined AVC as circumscribed changes of the aortic valve detected by echocardiography. Changes included marked increases in local thickness or echogenicity and no restriction of the aortic valve opening in the systolic phase. We also classified the severity of AVC according to the number of aortic valve leaflets with calcified lesions as 1, 2, or 3 affected leaflets. Figure 2 shows echocardiograms and MPS images of a representative case of AVC.

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FIGURE 2.

Representative case of aortic valve calcification. (A–C) Echocardiography shows focal area of increased echogenicity and thickness at noncoronary cusp of aortic valve (A and C, arrows). There are no restrictive leaflets, and valve opens well (B). (D) MPS shows extensive and severely reduced tracer uptake at lateral wall in stress images. Complete redistribution is observed in delayed images.

Adenosine Stress Test and SPECT Acquisition

All patients underwent an adenosine stress test in combination with low-level exercise (ergometry, 10 or 20 W), where possible. Adenosine was infused over 6 min (120 μg/kg/min), and ²⁰¹Tl (111 MBq [3.0 mCi]) was injected 3 min after the start of the adenosine infusion. During the stress test, blood pressure and 3-lead electrocardiographs were continuously monitored, and 12-lead electrocardiographs were recorded every minute during the procedure.

The stress ²⁰¹Tl SPECT acquisition was started almost 5 min after the end of the stress test. Four hours later, delayed ²⁰¹Tl SPECT images were also obtained. Electrocardiogram-gated SPECT images were acquired with a dual-detector 90° γ-camera system (E.CAM; Siemens Medical Solutions). Images were acquired with the following parameters: 32 total projections; 180° from right anterior oblique to left posterior oblique and a noncircular orbit; 64 × 64 matrix; 0.6-cm pixel size; 8 frames per cardiac cycle; low-energy, high-resolution collimation; and 40 s per stop. ²⁰¹Tl SPECT images were acquired with a 10% symmetric window over the 80-keV ²⁰¹Tl photopeak. The raw projection datasets were filtered with a Butterworth filter (order, 5; cutoff frequency, 0.65 cycles/pixel for rest and stress images). No scatter or attenuation correction was applied.

SPECT Interpretation

Semiquantitative visual interpretation of SPECT images was performed with the short and vertical long axes divided into 17 segments for each study, as recommended in guidelines from the American Society of Nuclear Cardiology (22). Each segment was scored using a 5-point scoring system (0, normal uptake; 1, mildly reduced uptake; 2, moderately reduced uptake; 3, severely reduced uptake; and 4, absence of detectable radiotracer in a segment). Tracer uptake in each segment was evaluated by 2 observers in consensus. The summed stress score (SSS) was obtained by adding the scores for the 17 segments of the stress ²⁰¹Tl SPECT images for each patient. If reduced tracer uptake was identified on stress images (SSS ≥ 1), reversibility of the defect was estimated as the summed difference score (SDS), which represents the extent and severity of ischemic myocardium. An SDS of 1 or 2 was considered to represent borderline ischemia, SDS ≥ 3 was defined as (any) myocardial ischemia, and SDS ≥ 8 was defined as moderate to severe ischemia for which revascularization was recommended (14,15). Only reversible abnormal defects were considered to represent inducible myocardial ischemia. Reverse redistribution on delayed ²⁰¹Tl SPECT images was not reflected in the SDS.

Statistical Analysis

Continuous variables are expressed as mean ± SD or median. Categoric variables are described as the number and percentage. After dividing the patients into 2 groups according to the presence or absence of AVC, continuous variables were compared using the Wilcoxon rank-sum test based on the distribution, and χ² tests were used for binary variables.

Multiple logistic regression analyses were used to calculate adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for the presence of myocardial ischemia (SDS ≥ 3), moderate to severe ischemia (SDS ≥ 8), and obstructive CAD. Analyses were adjusted for age, sex, hypertension, diabetes mellitus, dyslipidemia, hyperuricemia, chronic kidney disease, current smoking, and AVC. We also calculated ORs for a subgroup of asymptomatic patients.

All analyses were conducted using JMP statistical software (version 8.0.1; SAS Institute). P values of 0.05 or less were considered statistically significant.