Clinically silent myocardial infarctions in the CKD community

Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) are at a greater risk for incident myocardial infarction and death from coronary heart disease (CHD) compared with the general population [1]. The presence of CKD may accelerate the formation of vulnerable plaques, increase the frequency of plaque disruption and may increase thrombogenicity of the blood, making patients with CKD at high risk for myocardial infarction and mortality. Once diagnosed with CHD, patients with CKD have a greater incidence of recurrent cardiovascular events and mortality [2]. Research has suggested that CHD is unique in patients with CKD and ESRD compared with the general population with early onset, more rapid progression, atypical symptoms and higher rates of death. Although it is estimated that ∼13% of patients with CKD have suffered an acute myocardial infarction [3], it is likely that many patients with CKD have clinically silent CHD, which may have serious clinical implications on long-term cardiovascular morbidity and mortality. In a provocative study in this issue of NDT, Rizk et al. examine the prevalence and long-term impact of unrecognized myocardial infarctions among patients with CKD. In this large study of 18 864 patients with and without CKD enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, 12-lead ECGs were used to identify the presence of Q-wave abnormalities [4]. Recognized myocardial infarction was defined as the concurrence of self-reported myocardial infarction as well as Q-wave abnormalities on ECG, whereas unrecognized myocardial infarction was defined as the presence of diagnostic Q-wave abnormalities without self-report. The investigators report that, in patients with eGFR <30 mL/min/1.73 m2, the prevalence of unrecognized myocardial infarction was 13% compared with 4% in those without CKD [4]. The presence of macroalbuminuria was associated with a 10% risk of unrecognized myocardial infarction compared with 4% in patients without albuminuria. After 4 years of follow-up, the investigators found that among patients with CKD, the risk of death was similar in those with unrecognized versus recognized myocardial infarctions [4]. These compelling results suggest that unrecognized myocardial infarction appears to be more common in patients with CKD; and notably, unrecognized myocardial infarction conveys a similar negative prognosis compared with a clinically recognized myocardial infarction. This study makes an important contribution in being one of the first to define the burden of clinically silent myocardial infarctions in the CKD community. Several limitations of this study must be noted. The study cohort was primarily African-American (by design) so results may not be generalizable to other populations. This was a cohort that oversampled from the ‘stroke belt’ so participants likely had a higher prevalence of risk factors for stroke and thus CHD. The authors chose to utilize Q-wave abnormalities on baseline ECGs and self-report to define myocardial infarctions. However, in a cohort of patients sampled to study stroke, there may be issues with self-report of disease. Additionally, the significance of Q-wave abnormalities in representing prior myocardial infarction remains unknown in patients with CKD as patients with kidney disease are vulnerable to factors such as electrolytes abnormalities and fluid shifts, that may alter ECGs transiently. An alternative and perhaps more powerful strategy is to examine changes in serial ECGs as has been done in other studies [5–7]. Studies in the general population have also used sophisticated diagnostic tools such as cardiac magnetic resonance imaging to identify myocardial scarring as an indicator of prior myocardial infarction in patients with clinically silent CHD [8]. Finally, a more comprehensive evaluation of other abnormalities on ECGs, such as evidence of left ventricular hypertrophy for example, may help to elucidate the pathogenesis of unrecognized myocardial infarctions among participants with CKD. Although generally understudied, a few other studies have reported clinically silent or atypical presentations of CHD in patients with CKD and ESRD. One study of a small cohort of asymptomatic hemodialysis patients found that >50% had a significant CHD as diagnosed by coronary angiography [9]. In a collaborative study of the United States Renal Data System (USRDS)/Third National Registry of Myocardial Infarction (NRMI 2) Study, among patients hospitalized for acute myocardial infarction, the investigators found that only 44.4% of dialysis patients presented with chest pain (versus 68.3% of non-dialysis patients) and only 19.1% of dialysis patients had ST elevations (versus 35.9% of non-dialysis patients) [10]. The burden of asymptomatic CHD in CKD patients, however, remains largely understudied due to barriers such as reluctance to administer intravenous contrast dye needed for cardiac catheterization. However, one study of patients with and without CKD presenting with myocardial infarctions found that patients with CKD were less likely to report symptoms typical of myocardial infarction, such as chest pain, shoulder pain or arm pain [11]. These studies reveal that patients with kidney disease may be at high risk for atypical presentations or clinically silent CHD. Therefore, better understanding of the pathogenesis contributing to the development of CHD in patients with kidney disease is critical. The pathology of CHD differs in the presence of CKD and it is possible that this unique pathogenesis contributes to clinically silent CHD. Patients with CKD are vulnerable to accelerated arterial calcification with severe intimal-medial calcification [12] as well as atherosclerotic plaque formation. These parallel processes likely have distinct as well as shared risk factors, which are prevalent among patients with CKD, thus driving accelerated (and perhaps silent) CHD and mortality. Patients with kidney disease have a high prevalence of traditional risk factors such as older age, poorly controlled blood pressure and hyperlipidemia. In particular, the high prevalence of diabetes mellitus among patients with CKD may contribute to silent or atypical presentations of CHD [13]. Novel, kidney disease-related risk factors likely play a central role in promoting arterial calcification and plaque vulnerability to rupture and thrombosis (Figure 1) as well. In particular, CKD-related metabolic derangements have been associated with atherosclerosis and increased cardiovascular risk. Studies have shown that calcium phosphate (hydroxyapatite) precipitates in diseased coronary arteries by a mechanism similar to that found in osteogenesis and bone remodeling [14]. One of the principal stimuli for vascular calcium deposition appears to be activation of the Pit-1 receptor by phosphorus [15]. Thus, higher serum phosphorus concentrations have been linked to arterial calcification patients with CKD, even at phosphorus concentrations within the ‘normal’ laboratory reference range [16]. Studies have also found that vitamin D deficiency in patients with CKD is strongly associated with cardiovascular disease and mortality [17]. Fibroblast growth factor hormone (FGF)-23, a protein secreted by osteocytes which induces phosphaturia and inhibits conversion of vitamin D to the active form, is likely directly toxic to the cardiovascular system [18–20] and may induce vascular calcification [21, 22] although the exact mechanism remains unknown. The synergistic effect of these novel processes supposedly involved in CKD-related coronary atherosclerosis may potentially affect the manifestation and symptoms of CHD by altering the stability of coronary plaques in patients with CKD. Patients with CKD have accelerated coronary heart disease from the synergistic effect of traditional and novel cardiovascular risk factors. There is a higher prevalence of clinically silent coronary heart disease among patients with CKD compared with the general population, which may contribute to adverse cardiovascular outcomes and death. A possible approach to identify patients with CKD at risk for clinically silent CHD is to aggressively test for CHD, even in the absence of symptoms. However, our ability to diagnose CHD in patients with CKD remains limited. Tools such as the Framingham score have poor accuracy in predicting incident CHD in patients with CKD [23]. Biomarkers such as cardiac troponin measurements may have limited prognostic value as levels may be dependent on renal clearance [24]. Cardiac non-invasive diagnostic tests also have had limited prognostic use in patients with CKD. Exercise electrocardiography is limited by lack of specificity of the ST-segment response and by the inability of many CKD patients to reach a diagnostic exercise threshold [25]. The accuracy of pharmacological perfusion imaging is low in patients with CKD [25]. Stress echocardiography also demonstrates poor accuracy in CKD patients who often have the elevated left ventricular mass and small left ventricular cavity size [26]. Measurement of coronary artery calcium by computed tomography has yielded conflicting data in patients with kidney disease [27–29]. Use of contrast agents (due to concerns of contrast-induced acute kidney injury or other complications) limit the use of computed tomography coronary angiography and magnetic resonance imaging. Universal screening for CHD in patients with CKD and ESRD is controversial as the benefits must be balanced against the costs and possible side effects. Currently, there are several gaps in knowledge that pose a significant barrier in implementing universal screening tests including: (i) lack of effective CHD diagnostic tests designed for patients with kidney disease, (ii) insufficient evidence that CHD diagnostic testing predicts outcomes (iii) inadequate understanding of the burden of asymptomatic CHD in patients with CKD and (iv) the absence of cost-effective analyses of implementing universal CHD screening. Future studies in these areas may help guide recommendations on early diagnosis of CHD in patients with CKD and ESRD, thereby leading to opportunities for treatment and intervention. Primary treatment for CHD may have significant clinical impact in reducing the burden of clinically silent CHD in patients with CKD. In the past, there has been a dearth of randomized controlled trials to test primary cardiovascular treatment strategies in CKD and ESRD. Recently, the placebo-controlled Study of Heart and Renal Protection (SHARP) trial found that simvastatin plus ezetimibe reduced the incidence of major atherosclerotic events in a wide range of patients with advanced CKD [30]. This trial made great strides toward implementing evidence-based practices to prevent CHD in patients with CKD; however, further trials are urgently needed. For example, only one randomized trial of aspirin has included patients with CKD. Although this analysis found that patients with CKD receiving aspirin had a 45% lower risk of death [31], aspirin use still is limited in patients with CKD due to concerns of bleeding. Trials studying the short- and long-term impact of cardiovascular medications, targeted to reduce the burden of traditional as well as novel cardiovascular risk factors, are needed to potentially reduce the burden of clinically silent CHD in patients with kidney disease. Clinically silent CHD may lead to delay in the receipt of medical treatment and interventions for CHD, thus contributing to future complications such as recurrent CHD, other cardiovascular complications and death. Rizk et al. [4] noted that the mortality rates were similar among CKD patients with recognized versus unrecognized myocardial infarction. This is in contrast to some studies in the general population that have found that risk associated with clinically silent CHD is greater than recognized CHD [7, 8]. Future longitudinal studies are needed to expand on these results in patients with CKD and ESRD; it is quite possible that clinically silent myocardial infarctions have a larger scope of morbidity and mortality in patients with kidney disease than we are currently able to appreciate (Figure 1). For example, we recently reported that among patients with CKD, there was a strong, graded association between reduced estimated glomerular filtration rate and presenting with acute myocardial infarction versus stable exertional angina [32], suggesting that CKD is an independent predictor of more severe incident CHD; perhaps due to a high burden of clinically silent CHD prior to initial clinical presentation in patients with kidney disease. Silent coronary ischemia may also be responsible for the development of heart failure in patients with kidney disease. Sudden cardiac death is now the leading subset of cardiovascular disease in patients with kidney disease [33] and it is possible that clinically silent CHD is a significant contributor to this burden of disease. In males from the general population, clinically silent myocardial infarctions have been strongly associated with incident stroke and dementia [34, 35]; thus silent CHD may represent an important causal link between kidney disease and neurological disease. Therefore, identification and treatment of patients with CKD and ESRD with clinically silent CHD may have tremendous public health implications in reducing short- and long-term morbidity and mortality. CHD is unique in patients with CKD, with novel pathogenesis, accelerated progression and worse outcomes compared with the general population. However, the cumulative burden of CHD in the CKD community is likely underappreciated largely due to clinically silent CHD, as revealed by the thought-provoking study by Rizk et al. in this issue of NDT. Undoubtedly, diagnosing patients with CKD who have clinically silent CHD is challenging; however, the clinical implications of this unrecognized and untreated pathological process may be much greater than appreciated. Further longitudinal studies using sophisticated tools to identify clinically silent CHD are critical to understand the short- and long-term morbidity and mortality associated with this silent disease. A translational approach is needed to elucidate the contribution of novel cardiovascular risk factors on the pathogenesis and clinical presentation of CHD. Research to test CKD-specific diagnostic tools for early identification of patients at risk for CHD is crucial. Following the lead of the SHARP trial, further trials to test primary medical therapies to prevent CHD are needed. These research initiatives may enhance our ability to prevent, diagnose and treat CHD. Greater awareness of this burden of silent CHD is needed by clinicians, who in turn, must increase efforts toward primary cardiovascular counseling and management in patients with kidney disease. Future studies may reveal that the burden of clinically silent CHD is greater than we recognize in patients with kidney disease with tremendous clinical impact on morbidity and mortality. I would like to thank Dr Alan Go and Dr Chi-yuan Hsu for reviewing this editorial. Funding. Dr. Bansal is funded by K23DK088865 from the NIDDK. Conflict of interest statement. None declared. (See related article by Rizk et al. Prevalence and prognosis of unrecognized myocardial infarctions in chronic kidney disease. Nephrol Dial Transplant 2012; 27: 3482–3488.)