Aortic valve stenosis (AS) is the most common valvular heart disease and its incidence increases with age.1 Because the outcomes of AS are poor once symptoms develop, guidelines recommend aortic valve replacement (AVR) in severe, symptomatic AS.2,3 Angina pectoris is one of the symptoms of severe AS, even in patients without significant coronary artery disease (CAD).4,5 However, the incidence of angina pectoris and related CAD in patients with AS is not clear, especially in Asian countries.6,7 Therefore, there is continuing debate as to whether coronary angiography is necessary before AVR in patients with symptomatic AS.8–10 Some previous studies suggest that coronary angiography is needed only in patients with symptoms consistent with CAD,11 while others believe that it should be carried out only in those over 4012 or even 50 years of age,5 while others still conclude that coronary angiography should be performed in all patients before surgery.7,13,14 The purpose of this study is to evaluate the incidence of CAD and predictors of CAD in patients with severe AS in a Korean population.
Data from all consecutive patients with severe AS undergoing AVR at a major tertiary cardiac and vascular center in Korea were entered in a prospective registry beginning in 1995. We collected clinical and echocardiographic follow-up data on study patients and entered it into the database annually. We defined patients as having hypertension (HTN) if the patient was on antihypertensive medications at the time of admission or the past medical history/record documented an elevated blood pressure (BP) at multiple occasions, or if the BP was high (≥140/90 mmHg, 1 mmHg=0.133 kPa) on more than one measurement while admitted. Patients were counted as having diabetes mellitus (DM) when the patient was taking any antidiabetic agents or when the patient had the fasting blood glucose of ≥126 mg/dl or the random blood glucose of ≥200 mg/dl on more than two occasions. The patient had a positive family history of heart disease if any close relative <55 years of age in male or <65 years in female had a history of angina pectoris or myocardial infarction. We defined dyslipidemia in our patient cohort when total cholesterol was ≥240 mg/dl.15 Integrated echocardiographic evaluation was used to diagnose the severity of AS using the following measurements: aortic valve area <1 cm2, peak aortic velocity (AV Vmax) ≥4 m/sec, or a mean transaortic pressure gradient (AVmean PG) ≥40 mmHg). Patients are included in this study when they meet one of these criteria. We defined CAD as ≥70% narrowing in at least one coronary artery and ≥50% narrowing in left main artery on coronary angiography, because there is a general consensus that a luminal diameter reduction of 70% is needed to cause a hemodynamically significant reduction in flow in the coronary circulation.16 Exclusion criteria included other concomitant valvular disease of moderate or severe severity, coronary artery bypass graft, and prior valve surgery. The regional ethics committee approved this study. The patients provided informed consent before being enrolled into the study.
Comprehensive transthoracic echocardiography (M-mode, 2D, and Doppler) was performed using commercially available equipment (Vivid 7, GE Medical Systems, Milwaukee, WI, USA, or Acuson 512, Siemens Medical Solutions, Mountain View, CA, USA, or Sonos 5500, Philips Medical Systems, Andover, MA, USA). We recorded maximal aortic jet velocity from the apical, right parasternal, or suprasternal window that yielded the highest velocity signal.17 End diastole was defined as the frame with the largest cavity area immediately before the onset of the QRS and end systole as the frame with the smallest cavity area.2 Left ventricular (LV) end-diastolic volume, LV end-systolic volume, and left ventricular ejection fraction (LVEF) were calculated from 2D recordings using the modified biplane Simpson's method.2 Relative wall thickness and left ventricular mass were calculated as previously described.2 Left atrial volume was assessed by the modified biplane area-length method and was indexed to body surface area.18 Mean aortic gradient and aortic valve area (by the continuity equation) were obtained as previously reported and described in the guidelines of the American Society of Echocardiography. Early diastolic mitral inflow velocity (E) was measured using pulsed wave Doppler. The tissue Doppler-derived early diastolic mitral annular velocity (e″) was measured from the septal corner of the mitral annulus in the apical four-chamber view. We also measured the deceleration time of early transmitral flow velocity (DT). As an index of LV filling pressure, E/e″ was calculated.18,19 We used the average of three consecutive Doppler signals.
Coronary angiography was performed using standard interventional techniques with appropriate antiplatelet therapy and heparin use.20,21 All baseline coronary angiograms were reviewed and analyzed quantitatively at the angiographic core laboratory of the Samsung Medical Center (Seoul, Korea). CAD was considered hemodynamically significant if left main coronary arteries were estimated to have ≥50% narrowing of the lumen diameter and one or more major coronary arteries except for left main were estimated to have ≥70% narrowing of the lumen diameter from at least two views.
Carotid doppler ultrasonography
Vascular technologists performed carotid Doppler ultrasonography. The degree of carotid artery stenosis was defined according to the criteria set forth by the Society of Radiologists at the Ultrasound Consensus Conference. Critical stenosis was defined as ≥70% occlusion of the carotid artery.22 A carotid plaque was defined as the presence of focal wall thickening that is at least 50% greater than that of the adjacent carotid wall.
Continuous variables are listed as mean ± standard deviation (SD) or median. Categorical variables are presented as frequencies and group percentages. Differences between the significant CAD group and the non-significant CAD group were assessed using the Student's t-test for continuous variables and the χ2 test or Fisher's exact test for categorical variables. Logistic regression analysis was used to assess independent determinants of the presence of significant CAD. For multivariate analysis, statistically significant variables in univariate analysis and other important clinical variables irrespective of their univariate P values were included in the model. The discriminative power of the age that was accompanied by significant CAD in patients with severe AS was assessed with a receiver operating characteristic (ROC) curve. All reported P values were two-sided, and P <0.05 was considered statistically significant. SPSS 18.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.
Study population and clinical characteristics
From 1995 to 2012, 574 patients (mean age of (65.9±9.6) years) with severe AS who had undergone AVR met the criteria for inclusion in this study. The study population was divided into two groups based on the presence of significant CAD (CAD (+) group; (n=61, 10.6%), CAD (-) group; (n=513, 89.4%)). Patients with significant CAD had higher incidence of HTN (P <0.01), DM (P <0.01), dyslipidemia (P=0.002), chronic renal failure (P <0.01), carotid disease (P <0.01), and aorta calcification (P=0.020) than those without significant CAD. Mean age and EuroSCORE were higher in patients with significant CAD than in patients without significant CAD (Table 1). In the entire study population, the incidence of significant CAD increased with age (Figure 1A). In the 61 patients with significant CAD, ages were as follows: 3% (1 out of 32) age <50 years; 5% (5 out of 102) age 50–59 years; 9% (20 out of 218) age 60–69 years; 13% (24 out of 185) age 70–79 years; and 30% (11 out of 37) age ≥80 years (Figure 1A). Significant CAD was common in patients aged 70–79 years (Figure 1B). ROC curve analysis of our study population showed a better sensitivity (61%) for predicting critical coronary stenosis with an ideal cutoff value of 69.2 years (Figure 2).
Baseline characteristics and echocardiographic parameters of the non-significant CAD group and the significant CAD group are shown in Table 2. There were no differences in end-diastolic or systolic LV dimensions, wall thickness, left ventricular mass index, left atrial volume index, right ventricular systolic pressure, and LVEF. The presence of a regional wall motion abnormality was common in significant CAD group.
Causes of severe AS based on the presence of CAD
The cause of severe AS in all of our study patients with significant CAD was degenerative (100%). In the non-significant CAD group, causes of AS included degenerative (99%), rheumatic (0.8%), and active infective endocarditis (0.2%). Significant CAD was more common in patients with a tricuspid aortic valve than in patients with a bicuspid aortic valve. The proportion of patients without significant CAD who had bicuspid aortic valves was higher than the patients in the significant CAD group (P=0.001, Figure 3). Among patients with significant CAD, patients with bicuspid aortic valve were younger than those with tricuspid valves (Figure 4). Therefore, degeneration of the aortic valve seemed to be more related to the presence of significant CAD in severe AS patients.
Independent predictors of CAD in patients with severe AS
The incidence of severe AS increased every year, but the incidence of CAD in patients with severe AS did not (Figure 5). Coronary angiography findings in patients with severe AS were as follows: 66.9% (n=384) normal angiogram; 22.5% (n=129) angiogram not significantly abnormal; 5.9% (n=34) CAD in one vessel; 3.3% (n=19) CAD in two vessels; and 1.4% (n=8) CAD in three vessels. The incidence of adverse events during the period of hospitalization to receive the surgery did not differ significantly between the significant CAD and non-significant CAD groups (13.1% vs. 9.6%).
In Logistic regression analysis, the independent predictor of the presence of CAD in severe AS patients was age (P=0.011; Table 3). Between 1995 and 2012, the incidence of severe AS in our hospital increased. Depending on the age of the patients, the incidence of CAD in severe AS patients also increased in this population (Figures 1A and 5). ROC curve analysis of our study population showed a better sensitivity (61%) for predicting critical coronary stenosis with an ideal cutoff value of 69.2 years (Figure 2).
Incidence of significant CAD according to the presence of cardiovascular risk factors
The major risk factors for cardiovascular disease are old age, smoking, high BP, elevated serum cholesterol, and high plasma glucose. In multivariate analysis, we observed a significant interaction between the number of risk factors for cardiovascular disease and the incidence of CAD. An increased number of risk factors for cardiovascular disease have been associated with a higher incidence of significant CAD. If patients in our study had two or more risk factors for cardiovascular disease, the incidence of coronary artery stenosis increased significantly. If patients had four or more risk factors for cardiovascular disease, the rate of coronary artery stenosis was significantly higher (odds ratio=4.195, 95% confidence interval (CI)=2.142–8.214, P=0.005; Figure 6).
By ROC curve analysis, using two risk factors as the cutoff for cardiovascular disease risk was the most useful in predicting the incidence of significant CAD (Figure 7).
The main findings of our study in Korean patients with severe AS undergoing AVR are as follows: (1) the incidence of significant CAD was low, (2) the independent predictor of the presence of CAD was age, (3) that age significantly increased the incidence of significant CAD at 69.2 years, and (4) patients with a minimum of two risk factors for cardiovascular disease were more likely to also have significant CAD.
Presence of CAD in severe AS patients undergoing AVR
The presence of concomitant significant CAD in patients undergoing AVR worsens prognosis.5 Therefore, evaluation for the presence of significant CAD before AVR is necessary. Current updated guidelines suggest coronary angiography before valve intervention in patients with symptoms of angina, objective evidence of ischemia, decreased LV systolic function, history of CAD, or coronary risk factors (including men age ≥40 years and postmenopausal women) (Class I, Level of evidence C).23 CT coronary angiography is reasonable to exclude the presence of significant obstructive CAD in selected patients with a low/intermediate pretest probability of CAD (Class IIa, Level of evidence B). However, coronary angiography should still be carried out in all patients before AVR regardless of pretest probability of CAD due to the poor predictive value of angina pectoris and the lack of accuracy of available non-invasive tests.
In the Korean population, the incidence of CAD has been reported as 2.5%24 and has increased over time according to the Korean National Health Statistics, although this is still lower than rates of CAD in Western countries. The mortality rate of CAD has been reported as 52.5 people per 1 00 000.25 In this study, we aimed to investigate the incidence of CAD among Korean patients with severe AS who underwent coronary angiography before valvular surgery. The incidence of associated CAD in patients with severe AS has been reported to range from 21% to 56%.26 However, in our study the overall incidence of angiographically significant CAD was 10.6%. Therefore, although current updated guidelines suggest coronary angiography before valve intervention in patients with coronary risk factors (including men age ≥40 years and postmenopausal women, Class I, Level of evidence C), the incidence of CAD in Korea than in Western countries is low. So, age suggested coronary angiography before valve intervention in current updated guidelines could be higher in Korea than in Western countries.
The cause of severe AS in significant CAD patients
Severe AS is generally caused by degenerative or rheumatic causes or infective endocarditis. In our study, 100% of patients with significant CAD had a degenerative etiology for their severe AS. The high incidence of AS was associated with old age in our study population. This study demonstrated the frequent association of valve stenosis with coronary and extracoronary (carotid and aorta calcification) atherosclerotic diseases. These results support the recent hypothesis that calcification in AS is a presentation of atherosclerosis, with the process of valve fibrosis and calcification resembling the different phases of arterial plaque formation and progression.27,28 Thus, the pathophysiology of degenerative aortic valve disease is similar to that of atherosclerosis, which may be responsible for the relationship between AS and increased incidence of coronary artery stenosis.29
In a previous study, bicuspid aortic valves progressed more rapidly into regurgitation or stenosis, which resulted in a higher occurrence of AVR, especially at a younger age.30 In the present study, 55% of patients with severe AS were found to have a bicuspid aortic valve, which is comparable with previous reports.30,31 However, in this study, the incidence of CAD in patients with tricuspid valves was higher than in patients with bicuspid valves. Therefore, the incidence of CAD seemed to be more related to the degeneration of the aortic valve, and the incidence of CAD increased depending on age.
Predictors of the presence of CAD in severe AS patients undergoing AVR
The incidence of angina pectoris and related CAD in AS patients is not clear.6,7 Symptoms of angina pectoris have a low positive predictive value of CAD in patients with AS.32 Hence, the incidence of CAD in AS patients is difficult to discern from patient symptoms alone. This is one reason that coronary angiography should be carried out in all patients before AVR in clinical practice.
Current updated guidelines suggest coronary angiography is indicated before valve intervention in patients with symptoms of angina, objective evidence of ischemia, decreased LV systolic function, history of CAD, or coronary risk factors (including men age ≥40 years and postmenopausal women).23 Guidelines do not currently suggest the number of coronary risk factors for predicting the presence of CAD. In general, the incidence of CAD increases progressively with the number of coronary risk factors. In our study population, conventional risk factors for CAD were more prevalent in the significant CAD group, including age, smoking, HTN, DM, and dyslipidemia. Previous studies found that the incidence of CAD increased progressively with an increase in the number of coronary risk factors, whereas the incidence was low in patients without angina or coronary risk factors undergoing routine coronary angiography before AVR.33 In our study population, if a patient had two or more risk factors for cardiovascular disease, the incidence of coronary artery stenosis increased significantly. If a patient had four or more risk factors for cardiovascular disease, the rate of incidence of coronary artery stenosis was even higher. By ROC curve analysis, using two risk factors for cardiovascular disease as a cutoff value to predict the incidence of significant CAD was the most useful.
According to a previous study, CAD has been reported in ≥50% of patients with AS ≥70 years of age and in ≥65% of patients ≥80 years of age.32 In our study population, ROC curve analysis showed a better sensitivity (61%) for predicting critical coronary stenosis with an ideal cutoff value of 69.2 years. Previous reports imply the rationalization of the diagnostic methods because of the limited value of age criteria in the ideal time of conventional coronary angiography.
The extent of CAD involvement in patients with severe AS predicts morbidity and mortality associated with AVR and is also important for the assessment of long-term prognosis.8,34 Thus, patients with severe AS scheduled for AVR should routinely undergo coronary angiography. The incidence of significant CAD in Korean patients with severe AS was low in this study and in some previous studies. Therefore, in patients with a low/intermediate pretest probability of CAD such as in Asian countries, CT coronary angiography is reasonable to exclude the presence of significant obstructive CAD in patients who are young or have few risk factors.
Patients included in this study were consecutively enrolled at a single center in Korea. We cannot assume these results represent other hospital patient populations in Korea or other Asian countries. We excluded patients with multiple valve disease and significant aortic regurgitation. However, in a previous study, it has been reported that patients with severe AS were associated with aortic regurgitation. So, we might have underestimated the incidence of patients with severe AS. However, we believe that the incidence of significant CAD in the general population and in patients with severe AS is quite similar in other Asian countries. Large-scale, multicenter studies will be needed to confirm these results.
The incidence of significant CAD in patients with severe AS was low in a Korean population; in our study, the overall incidence of angiographically significant CAD was 10.6%. Therefore, coronary angiography before AVR will be considered in patients with multiple risk factors for cardiovascular disease or in patients more than 69 years of age without risk factors for cardiovascular disease.
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