Cardiac amyloidosis is the most common type of infiltrative cardiomyopathy, which represents various clinical manifestations such as congestive HF, arrythmia, orthostatic hypotension, syncope or even other system expressions like gastro-intestinal symptoms, albuminuria, and carpal tunnel syndrome leading to a large increase in the rate of missed diagnosis [1]. In the present study, we analyzed serum CA125 levels in 101 consecutive cardiac amyloidosis patients at an expertise center in China. To the best of our knowledge, this is the first study to analyse the prevalence and evaluate the clinical significance of serum elevated CA 125 levels in patients with cardiac amyloidosis. The principal results of this study are as follows: 1) serum CA 125 levels were elevated in more than a half of cardiac amyloidosis patients, compared to those with normal CA 125 levels, patients who exhibited high serum CA 125 had higher levels of hemoglobin, potassium, low density lipoprotein-cholesterol, total cholesterol and cardiac troponin T, as well as more common with polyserositis and low limb voltage; 2) the values of CA 125 in cardiac amyloidosis patients were significantly higher than in patients with MM and AHF; 3) CA 125 was a significant independent predictor of survival, with higher levels being independently concerned with lower overall survival; 4) as a predictor of the prognosis, CA 125 has no worse prediction accuracy than cardiac troponin T, NT-proBNP and LDH according to the AUC, in addition, it does not seem to be affected by estimated Glomerular Filtration Rate (eGFR) of patients.
Serum CA 125 values are used in the diagnosis and follow-up of the patients with ovarian cancer and to evaluate the response to therapy [18, 19]. It is reported that elevation of serum CA 125 also has been observed in other malignancies [20–24] and non-malignant diseases [25–28]. The first study regarding the underlying influences between CA 125 and cardiovascular system investigated the association of serum CA 125 levels and pericardial effusion in 1993 [29]. Whereafter, Nägele et al. [17] showed for the first time a systematic relation to serum values of CA 125 and HF in 1999, concluded that CA 125 may be a valuable tool for the monitoring of the status and clinical course of patients with HF or even influence the drug therapy and decision for heart transplantation. A study analyzed [16] a series of tumor marker levels in patients with chronic HF (CHF) also demonstrated that only CA 125 levels correlated with baseline clinical status in HF compared with CA 19 − 9, CA 15 − 3, carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP). D'Aloia et al. [14] and Kouris et al. [15] found that serum CA 125 levels of patients with CHF were significantly higher in NYHA class Ⅲ/Ⅳ compared with those in NYHA class Ⅰ/Ⅱ. Furthermore, in addition to CHF, elevated CA 125 values were also observed in AHF and used to assess 6-month risk stratification in patients admitted with AHF [30]. At present, some studies have confirmed that cardiac troponin T and NT-proBNP have significant clinical values in determining the prognosis for newly diagnosed AL amyloidosis patients, accordingly, the Mayo Clinic established a staging system involving the two biomarkers (as well as free light chain) to predict patient outcomes [31, 32]. This risk stratification system is also the most commonly used in clinical practice.
The potential mechanism of serum CA 125 levels elevation in cardiac amyloidosis remains unclear. Seo et al. [29] found that among 57 patients with different etiologies of pericardial effusion, 65% had significantly higher serum CA 125 levels than normal, moreover, with the reduction or disappearance of effusion, the levels of CA 125 were reported to decrease or even normalize. In addition, they also used anti-CA 125 antibodies to stain the pericardial tissue obtained at autopsy of 17 patients and showed higher serum CA 125 levels in the CA 125-positive-stained pericardium than compared to those in negative for CA 125. Except for pericardial effusion, elevated serum CA 25 levels have also been reported in pleural and peritoneal effusions with non-malignant diseases and demonstrated that CA 125 might be produced from the mesothelial cells of pleura and peritoneum [33–35]. Consistent with the present study, polyserositis were observed in 79.3% of 58 cardiac amyloidosis patients with elevated CA 125 levels in our findings. On the other hand, some studies indicated that blood levels of cytokines and/or its receptors such as IL-6, IL-10 and TNF-α were more likely to be increased in patients with HF and the cytokine network activation is one of the main factors for serum CA 125 elevation in patients with CHF dependent on inflammation [36–38]. Compared to patients with AHF, serum CA 125 levels with cardiac amyloidosis were significantly higher in our study (p < 0.01), although the blood mean levels of CA 125 in AHF above normal. Meanwhile, we found that only 3 patients with MM had a mild elevated in serum CA 125 levels (p < 0.01), so we mainly excluded the effect of plasma cell diseases on CA 125. Based on the studies and our findings, it could be hypothesized that the reasons for the elevation of serum CA 125 levels in cardiac amyloidosis might be as follows: 1) abnormal deposition of amyloid in the serosal tissue and increased chronic left ventricular filling pressure caused by HF leading to tissue streching and stimulate the secretion of methoselial cells; 2) amyloid activates the cytokine network by inflammation excitation and stimulate the methoselial cells to produce and secrete CA 125. However, the underlying mechanism linked between CA 125, cytokines, CA 125-producing cells and cardiac amyloidosis needs further study to illustrate.
Our study found that the levels of cardiac troponin T are associated with the serum CA 125 levels, as the higher cardiac troponin T levels in high serum CA 125 group compared to normal CA 125 group. We speculated that patients with elevated serum CA 125 could have more fluid accumulation leading to increased left ventricular filling pressure and polyserositis, which caused increased wall stress due to diastolic dysfunction and compressed myocardial capillaries, induced deficient myocardial blood supply and myocardial ischemia. Similarly, we also discovered that patients with high serum CA 125 values had higher levels of hemoglobin, potassium, low density lipoprotein-cholesterol, total cholesterol. We conjectured that most of the cardiac amyloidosis patients with elevated CA 125 levels have involved the kidney, and combined with nephrotic syndrome [39], which caused body fluid to enter the interstitial space or serous cavity, leading to blood concentration and dyslipidemia. Of course, the significant difference between the serum CA 125 levels of low limb voltage could also be explained by serous effusion. Nevertheless, further pathophysiological mechanisms need to be confirmed by subsequent studies.
CA 125 was significantly contributed to prognosis after adjusting for systolic blood pressure, diastolic blood pressure, hyperlipidemia, treatment without chemotherapy, low-density lipoprotein-cholesterol, total cholesterol, left ventricular posterior wall, and low limb voltage. The median overall survival of high levels of CA 125 patients was only 5 months while there were 20 months of median overall survival in normal CA 125 levels. It means high levels of serum CA 125 are independently concerned with high mortality in patients with cardiac amyloidosis. The accuracy of CA 125 in predicting the overall survival was not inferior to the classical prognostic biomarkers including cardiac troponin T, NT-proBNP and LDH in this study. In addition, the possible preponderance of CA 125 in contrast with those biomarkers maybe its easily obtainable, repeatable, no preparations and inexpensive cost (less than 4 dollars per determination in China compared with more than 40 dollars about NT-proBNP). Meanwhile, it is reported that the CA 125-guided therapy (keeping CA 125 levels at 35 KU/L or less by optimizing the use of diuretic, enforcing the use of statins and increasing the frequency of monitoring visits) was superior to the standard of care for AHF by reducing the risk of one year death and the rate of rehospitalization [40]. Maybe in the future, we can also adjust the treatment strategy for patients with cardiac amyloidosis to reduce the myocardial injury, improve the clinical condition of patients, assist chemotherapy and decrease the rate of mortality and readmission based on serum CA 125 values.