The purpose of our study was to evaluate the impact of CKD on the clinical stability and the initial clinical presentation of CHD (acute myocardial infarction versus stable exertional angina). We chose patients who presented with stable exertional angina as a control group to isolate risk factors for clinical instability of CHD rather than underlying coronary atherosclerosis. Our results suggest that the risk of presenting with acute myocardial infarction (compared with stable exertional angina) is greater in patients with CKD, particularly below eGFR of 45 ml/min/1.73m2. The odds ratio of this association increased by nearly threefold after adjustment for sociodemographic and lifestyle characteristics, traditional cardiovascular risk factors and pre-event use of a wide range of relevant medications (). These results suggest that there may be alternative mechanisms related to CKD that promote plaque instability and subsequent myocardial infarction.
Coronary atherosclerosis is a spectrum of disease, ranging from clinically stable plaques to vulnerable plaques susceptible to rupture and thrombosis. The initial expression of CHD is largely dependent on the stability of these atherosclerotic plaques. The severity and stability of the initial presentation of CHD significantly impacts clinical management and long-term cardiovascular outcomes. Certain populations have unique manifestations of CHD. Our study suggests that patients with CKD may have distinct risk factors for plaque vulnerability.
To our knowledge, no other studies have evaluated the impact of CKD on the clinical stability and presentation of CHD. CKD has been a well-described risk factor for atherosclerosis and CHD, with cardiovascular disease causing the greatest mortality in the CKD population.(6
) A key understudied question has been whether high cardiovascular disease morbidity and mortality in this unique population is a result of both more frequent cardiovascular events(6
) as well as more severe events. Our results support the hypothesis that patients with CKD appear to have greater likelihood of more clinically unstable and severe disease. Our results also suggest that clinical efforts should be targeted to identify this high risk population before incident symptoms of atherosclerosis occur and that we should aim to develop effective interventions and strategies to shift the expression of CHD from acute myocardial infarction to more stable presentations in patients with CKD.
Several mechanisms can be postulated to possibly explain the association between reduced eGFR and greater risk for acute myocardial infarction. In addition to the high prevalence of “traditional” risk factors, such as hypertension, hyperlipidemia and diabetes, CKD patients often have unique pathophysiologic mechanisms that may play important roles in the initiation and acceleration of cardiovascular disease. It is possible that these CKD-related mechanisms may also promote plaque vulnerability to rupture and thrombosis. For example, it appears that atherosclerotic plaque morphology in ESRD is accompanied by marked sub-intimal calcification and medial thickening as a result of hypertrophy and hyperplasia of vascular smooth muscle cells, causing arterial stiffness which may affect plaque formation. Elevated pulse pressure may be a reflection of this arterial stiffness and has been an indicator of increased risk of cardiovascular events and mortality for patients on hemodialysis.(18
) Also, anemia in patients with kidney disease has been strongly associated with increased cardiovascular and all-cause mortality in patients with CKD and ESRD and may increase plaque instability.(20
) Additionally, CKD-related metabolic derangements have been associated with increased cardiovascular mortality; for example hyperphosphatemia may contribute to arterial calcification, although the exact pathogenesis is not known.(22
) Inflammation has also been shown to be closely related to cardiovascular death in the CKD and ESRD population.(26
) Models have shown that various inflammatory markers are elevated in CKD and may enhance production of free radicals that increase atherosclerosis. Inflammation may also alter plasma protein composition and endothelial structure to promote vascular disease.(28
) The synergistic effect of these novel processes may accelerate coronary atherosclerosis in CKD patients and potentially affect the type of clinical presentation of CHD by altering the stability of coronary plaques and vascular function.
Our study had several strengths. Our study population was a large and diverse sample of well-characterized community-based patients. We were able to capture incident clinical CHD by symptoms and diagnostic tests such as cardiac enzymes and electrocardiograms, with careful phenotyping of the clinical presentation of CHD. We also had calibrated outpatient serum creatinine measurements available before the index cardiac event. Our study had several limitations as well. The exact mechanism of the association between CKD and clinically unstable CHD cannot be delineated from our study. For example, information on circulating inflammatory or pro-thrombotic factors was unavailable prior to the index event. The timing of the last outpatient creatinine measurement varied in the study population, and use of a single measurement could have led to some misclassification in eGFR level even though we relied on outpatient, non-emergency department serum creatinine measurements that likely reflected steady-state renal function. Data on urinary protein excretion were unavailable. We also could not determine the use of pre-event aspirin in our study population as it was not available in our health plan databases because it is routinely used as an over-the-counter medication. Patients with acute myocardial infarction or stable angina who died before attempted contact were not enrolled which may contribute to spectrum bias. There may be other residual confounders for which we were unable to identify and adjust for. While we found no evidence of poor model fit, the Hosmer-Lemeshow goodness-of-fit test has limited power to detect poor fit in certain circumstances. Finally, we conducted our study among health plan members within a large integrated health care delivery system in Northern California, so our findings may not be completely generalizable to other health care settings or to uninsured patients.
In conclusion, reduced eGFR was associated with a greater likelihood of presenting with acute myocardial infarction versus stable exertional angina among patients with new-onset symptoms of CHD. Our study suggests that patients with kidney dysfunction are at substantially higher risk for severe, clinically unstable CHD that are not explained by known clinical cardiovascular risk factors and other major confounders. Our results support the need to focus our efforts towards early identification of this high-risk population and the development of effective targeted cardio-preventive interventions to reduce the risk of irreversible cardiovascular complications.