Our results suggest that not only LMW Lp(a) and LRLC—which are independent predictors for the onset of CHD—but also the combination thereof more strongly predicts CHD. We used the Cox proportional hazard model to analyze LMW Lp(a), LRLC, and LMW Lp(a) + LRLC. When not adjusted, hazard ratio for LMW Lp(a), LRLC, and LMW Lp(a) + LRLC were, 4.45, 3.45, and 11.31 respectively. When adjusted for age, female gender, CRP, ACE-I/ARBs, SBP, HDL-C, HbA1c, and CKD II/III, hazard ratio for LMW Lp(a), LRLC, and LMW Lp(a) + LRLC were, 4.31, 3.62 and 7.15, respectively.
Many previous studies have reported that the incidence of CHD was significantly higher in the elevated Lp(a) group [13, 14, 28]. Furthermore, Lp(a) has been reported to compete with plasminogen for the binding sites in a dose-dependent manner. In addition, the risk of developing CHD due to Lp(a) was attributed to the amount of Lp(a) that was bound to small-size apo(a) . In the present study, therefore, we investigated how Lp(a) phenotypes, but not serum Lp(a) concentrations, might influence the onset of CHD. We also speculated that every phenotype presents genetic polymorphism as described by Ichinose et al. . Consequently, not only serum Lp(a) concentrations but also Lp(a) phenotypes were found to be associated with the onset of CHD.
We consider that LRLC is a predictor of CHD based on its diagnostic usefulness according to previous studies (5,6,7,11), as well as on the correlation coefficients of CHD (Table 2) and the results from the ROC analysis about blood cell markers in the present study. Data from experimental work in animals and in vitro data show that leukocytes also play an important role in atherogenesis . Furthermore, previous investigations have demonstrated that LRLC is also an independent predictor for CHD [5, 7]. Our results indicated that subjects with LRLC had an adjusted 3.62-fold hazard ratio of developing CHD events during follow-up and that LRLC was an independent predictor for CHD. Our data support at least partially the role of leukocytes in the chronic process of atherosclerosis. Although pathophysiological mechanisms still remain unclear, current evidence suggests that LRLC may be useful for identifying patients with heart disease, e.g., ACS and heart failure. To the best of our knowledge, however, no previous study has examined whether LMW Lp(a) and LRLC, when combined, are strong and independent predictors for the onset of CHD. Our study is the first to address this issue.
According to many previous studies, the causes of lymphocytopenia are regarded as an early marker of stress because the stress-induced increase in cortisol secretion leads to lymphocytopenia [32, 33]. The mechanism to induce changes in leukocyte counts probably involves interactions among the nervous, endocrine, and immune systems that differ from the electrical and cell-damage mechanisms for electrocardiographic and biochemical markers of infarction . The hypothalamus responds by increasing serum corticotropin-releasing hormone levels, which then causes pulsatile increases in serum cortisol levels.
Not only physiological stress but also mental stress has been speculated to provoke the rupture of the fibrous cap around coronary atherosclerotic plaque . Black PH et al. hypothesized that stress induces the release of cytokines, which, together with major stress hormones—corticosteroids and catecholamines, induces the production of acute phase proteins in the liver  and that various classes of stress can induce the production and release of proinflammatory cytokines which may mediate micro thrombosis.
There are several limitations to our study. First, we enrolled outpatients in a prospective open-label trial, which may potentially involve attribution biases. Furthermore, our study cannot rule out the presence of selection bias due to its nature of being a hospital cohort study. Second, sample size for the onset of CHD may be small. Therefore, a multicenter study enrolling a greater number of patients will be required in the future. Furthermore, high-sensitivity CRP could not be measured. There is also a need to determine the number of lymphocyte count measurements by multiple measurements in the future. Third, we did not measure serum cortisol levels to confirm its elevation in association with a reduction in RLC. To the extent possible, patients with heart failure (NYHA II or greater) were excluded. However, ejection fraction (EF) was not determined at baseline. Finally, several Lp(a) phenotypes are considered to exist. A further effort should be made to determine whether other unknown Lp(a) phenotypes may or may not correlate with the onset of CHD. Moreover, further study using analytical procedures (e.g., pulse-field electrophoresis of unamplified genomic DNA) will elucidate the effects of Lp(a) with a specified number of KIV-2 repeats on CHD in the future.