Discussion
We quantified the AVA index by transthoracic echocardiography in consecutive patients receiving coronary angiography and clarified that CKD, even pre-stage 5 CKD, was the most powerful determinant of AVA index among a high risk population for coronary atherosclerosis.
Calcific aortic valve disease is frequent in the general population and is associated with high cardiovascular risk [
1,
2]. This valvular disease is a slowly progressive disorder with a disease continuum that ranges from mild valve thickening without obstruction of blood flow, termed aortic sclerosis, to severe calcification with impaired leaflet motion, or AS [
21]. The pathologic mechanisms involved in the disease include active processes that are similar to those occurring in coronary atherosclerosis, such as the impairment of endothelium, inflammation, and lipid infiltration [
21‐
23]. Thus, calcific aortic valve disease has been widely shown to correlate with the presence and severity of CAD [
3,
24,
25].
Despite the similarities in the histopathologic features and clinical factors associated with calcific aortic valve disease and coronary atherosclerosis, however, discrepancies also exist. For example, although calcific changes can be seen in the atherosclerotic plaques of coronary arteries, calcification occurs earlier and is a more prominent feature of calcific aortic valve disease, particularly in the end stages of the disease process, and a large contributor of disease progression is prominent calcification with a gradual increase in leaflet thickness and outflow obstruction [
26]. The importance of tissue calcification in the disease process is highlighted by the observation that subsets of patients with altered mineral metabolism such as CKD have a higher prevalence of calcific aortic valve disease and more rapid disease progression [
6‐
9]. However, most previous studies have demonstrated an association between end-stage renal disease and calcific cardiovascular disease, especially in patients on dialysis [
6‐
9], and therefore, less is known about the impact of early stage CKD on the prevalence and severity of calcific aortic valve disease. The present study indicates that patients with early stage CKD have an increased prevalence of AS in the populations at high risk for coronary atherosclerosis. Notably, most of patients with CKD in the present study were in stage 3, and mean eGFR in patients with and without AS was 64 ± 23 and 53 ± 18 ml/min/1.73 m
2, respectively, suggesting that small differences in renal function in early stages CKD can contribute to the progression of calcific aortic valve disease in patients at high risk for coronary atherosclerosis. Although it would be difficult to address the underlying mechanisms that are responsible for the progression of calcific aortic valve disease in these earlier stages of CKD, the present study suggests that latent alterations in multiple factors such as inflammation, anemia, oxidative stress, abnormal calcium/phosphate metabolism, and hemodynamic overload may interdependently contribute to the disease process, even when serum calcium/phosphate levels are within normal ranges, and c-reactive protein levels, hemoglobin levels, and echocardiographic parameters of LV filling pressure are statistically similar between patients with and without AS. Although the present study did not focus on activation of proinflammatory mechanisms as a causal mechanism for the progression of calcific aortic valve disease, Aikawa et al demonstrated that proinflammatory cathepsin S, a highly potent elastase, contributes to arterial and valvular calcification in mice with atherosclerosis and CKD assessed by in vivo and ex vivo optical molecular imaging [
27]. They used molecular imaging of early calcification and elastolytic activity to address new mechanisms underlying accelerated calcification in patients with CKD and suggested that calcification is a multifactorial process induced by proinflammatory stimuli that promote accumulation of elastolytic macrophages. Although the present study did not focus on abnormalities in mineral metabolism as a causal mechanism for the progression of calcific aortic valve disease, previous clinical studies have demonstrated that a decrease in 1,25-dihydroxyvitamin D and an increase in parathyroid hormone (PTH) are the earliest mineral metabolic events that take place in CKD, while serum calcium and phosphate levels are altered later in the course of CKD [
28]. Adeney et al. demonstrated that higher serum phosphate concentrations within the normal laboratory range were associated with a statistically greater prevalence of coronary artery, descending thoracic aorta, and mitral valve calcification in a community-based cohort of individuals with moderate CKD and no clinically apparent cardiovascular disease [
29]. A decline in renal function leads to phosphate retention, elevated PTH levels, and low 1,25-dihydroxy vitamin D levels; however, serum phosphate levels are often maintained within the normal laboratory range until relatively late in the course of CKD [
30‐
32]. Therefore, evaluation of the levels of serum PTH and 1,25-dihydroxy vitamin D, early markers for impaired mineral metabolism, is important to clarify the underlying mechanisms that are responsible for the progression of calcific aortic valve disease in early stage CKD.
Several studies have documented an overlap in the clinical factors traditionally associated with calcific valve disease and coronary atherosclerosis [
33‐
38]. In the prospective population-based Cardiovascular Health Study, which included 5621 adults over the age of 65 years, clinical factors associated with calcific aortic valve disease included age, gender, smoking, hypertension, and hyperlipidemia [
33]. However, CKD was not included as a potential contributor to aortic valve calcification and stenosis in these studies. In contrast, our study demonstrated that conventional risk factors for cardiovascular atherosclerosis were not independently related to the progression of aortic valve disease, possibly because they were well-controlled. Despite receiving adequate risk factor management, more than half of the patients developed CKD in the present study, and CKD, even pre-stage 5 CKD, has a more powerful impact on the presence and severity of AS than other conventional risk factors for atherosclerosis in patients at high risk for CAD. These results indicate that patients with CKD should be included as part of the highest risk group for the progression of calcific aortic valve disease. Aortic valve calcification impairs the movement of aortic valve leaflets, which affects cardiac function, and can only be alleviated through costly and invasive procedures. Therefore, early diagnosis of and interference with aortic valve calcification could provide enormous clinical benefits.
Although 34% of patients were diagnosed with AS based on AVA, the average value of their peak velocities and mean pressure gradients across the aortic valve were only 1.70 ± 0.41 m/sec and 6.20 ± 3.28 mmHg, respectively. Patients with AS in our study population were older, had smaller body size, were more often women, and had smaller LVOT diameter compared with those without AS, which may partially be associated with low-flow and low-gradient AS [
39]. Nevertheless, the present study demonstrated that presence of both with CKD and CAD had a great impact on reduced AVA index and elevated peak velocity across the aortic valve.
A potential limitation of the present study was the small sample population, although we succeeded in testing our primary hypothesis, which showed the impact of CKD on the presence and the severity of AS in patients at high risk for CAD. Three dimensional measurements of LVOT and aortic valve area were not involved in this study. However, Doppler-derived estimation of AVA using two-dimensional transthoracic echocardiography is considered to correlate well with simultaneous catheter-derived measurements, and is widely used clinically [
14‐
16]. Invasive pressure measurements were not involved in the present study; therefore, evaluation of AVA using Gorlin's formula was not possible. Also, direct measures of LV end-diastolic pressure or pulmonary wedge pressure were not possible. Accordingly, E/E' was recruited as a marker of LV filling pressure in the present study [
17,
18]. Finally, evaluation of the rate of progression of aortic stenosis or the clinical outcome was not included in our study. The long-term effect of CKD on the progression of calcific aortic valve disease warrants further investigation.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
CM, YS, YB, HF, and SF acquired the ultrasound images and performed the analysis. CM and KD contributed substantially to data interpretation and wrote the manuscript. KD contributed substantially to the conception and design of the study, and critical revision of the manuscript for important intellectual content. TS and MS assisted in data interpretation. KO and KS contributed to critical revision of the manuscript for important intellectual content and study supervision. MI and TN reviewed the manuscript. Finally, all authors read and approved the manuscript.