In recent years, advanced treatment have reduced the mortality and improved the quality of life for patients with heart failure. However, altered hemostasis and abnormalities in endothelial function are thought to be other possible mechanisms that contribute to disease progression, ischemic events, and intracardiac thrombosis in heart failure . HF is associated with an increased risk of venous thromboembolism (VTE) as a result of vascular abnormalities, increased coagulability, and impaired blood flow . VTE includes two main clinical manifestations, deep vein thrombosis (DVT) and pulmonary embolism (PE), leading to a higher mortality in heart failure . Patients with heart failure have a higher risk of VTE than those without heart failure, and the risk increases with the severity of heart failure. D-dimer is a product of the degradation of cross-linked fibrin and its plasma levels reflect both fibrin formation and degradation, and hence, D-dimer is elevated when there is thrombosis in the whole circulatory system. D-dimer is considered a useful biomarker worthy of continued attention because of its potential to identify patients with hypercoagulability . Alexandre and Theodore E. et al. who evaluated 2593 hospitalized HF patients, observed an positive association between HF severity and both VTE risk and D-dimer concentration . Marcucci et al. found that D-dimer levels increasd significantly in acute decompensated HF patients . In addition, In the study of Ali Zorlu, it was shown that D-dimer was predictive of mortality in patients with systolic HF . In consistent with the previous studies, our data suggested that plasma D-dimer levels were elevated in patients with HF. Importantly, patients with the higher levels of D-dimer were accompanied by high New York Heart Association (NYHA) founctional calss. Furthermore, our study showed that a elevated D-dimer level associated with an increased risk of all-cause death in elderly patients with CHF during 2 years follow up (Fig. 3).
Generally, the patients with HF were often accompanied by a disorder of protein metabolism. Albumin as the most represented plasma protein plays a pivatal role in the maintenance of homeostasis and physiological functions . Serum albumin as a nutritional marker is related to cardiovascular mortality as well as important survival determinants and indicators for hemodialysis patients . Hypoalbuminemia is common in elderly HF patients with a prevalence of 25–42% . Previous studies also showed that hypoalbuminemia was associated with cardiovascular disease in the general population and adverse outcome in patients with HF independent of natriuretic peptides . Arnaud et al studied 546 patients with HF, and found that 64.8% patients with a serum albumin lower 38.7 g/L and hypoalbuminemia (< 34 g/L) yielded the best sensitivity (78.8%) and specificity (75%) for predicting hospital death . A retrospective studies in a real-world cohort of patients with HF performed by Israel et al demonstrated that decreasing albumin levels were directly associated with reduced survival and serum albumin is a significant predictor of a worse outcome in these patients . Another study done in 177 patients with acute decompensated heart failure (ADHF) performed by Megan M et al showed that baseline serum albumin concentration of 30 g/L or less had a value for predicting worsening renal function in patients with ADHF . The finding is consistent with our belief, our data suggested that patients with HF had a less serum albumin level compared to the threshold, 36.44 ± 4.60 g/L and 40 g/L, respectively. And about one hundred thirty-three patients (75%) had a serum albumin value less than 40 g/L. Additionally, our results showed that the serum albumin level were negatively significant associated with both elevated D-dimer and plasma D-dimer levels on univariate analysis. Furthermore, multivariate analysis showed that the serum albumin level was independently related to elevated D-dimer levels. Several mechanisms have been proposed to explain the association between hypoalbuminemia and plasma D-dimer, including hypoalbuminemia-induced hypercoagulability and thrombosis [22, 23]. Data from Bang et al and Iioka Y et al showed negative correlations between serum albumin level and plasma D-dimer level in patients with nephrotic syndrome [24, 25]. A similar result was obtained by Remuzziet al . Combined with the negative correlations between plasma D-dimer and serum albumin found in this study, which have also been indicated by Soon Bae Kim et al , we speculated that elevated plasma D-dimer in HF may be partially related to hypoalbuminemia-induced hypercoagulability.
Prealbumin (PAB) is another indicator of nutritional status, similar to albumin, also known as transthyretin. Compared with albumin, PAB has the advantages of shorter half-life and smaller serum pool. Its main functions are to bind and transport endogenous proteins and small molecules. Thus, PAB is more sensitive to changes in acute protein status . Previous studies have shown that prealbumin is most commonly used as an indicator of malnutrition, and hypoalbuminemia has an adverse effect on disease outcomes because of increase in incidence of infection, length of hospital stay, and risk of death . Andreia et al found that hypoprealbuminemia are more susceptible to early posttransplant thrombotic complications, particularly hepatic artery thrombosis which correlates with high morbidity, in patients with hereditary transthyretin amyloidosis (ATTR) . Patrícia and his colleagues showed that prealbumin is an independent predictor of in-hospital mortality in HF patients . Furthermore, they suggested that prealbumin levels below a cut-off < 15 mg/dL were found to be associated with reduced survival and increased rates of all-cause and HF readmission at 6-month follow up . In consistent with the previous studies, our finding using multivariate linear regression analysis showed that the serum prealbumin level was inversely related to elevated plasma D-dimer levels after adjustment for multiple variables including age, gender, HF risk factors, and medicine treatment. More interestingly, our data showed that elevated D-dimer level was with a lower serum prealbumin level about 15.3 mg/dL.
Blood urea nitrogen (BUN) as a nitrogenous end product of protein metabolism has been observed to be associated with mortality in various diseases . A large body of evidence have demonstrated that elevated BUN levels are associated with adverse outcomes in patients with HF, especially in acute decompensation state [34, 35]. The ACTIV study showed highest BUN quartile had the highest 60-day mortality, more importantly, BUN was a predictor of the composite end point of mortality and 60-day post-discharge death or hospitalization for chronic heart failure . Fonarow et al identified BUN level of 43 mg/dL on admission as the best single indicator between hospital survivors and nonsurvivors by evaluating the Acute Decompensated Heart Failure National Registry (ADHERE) database. Of note, they suggested that BUN may be a stronger predictor of outcomes . In a total of 541 patients with decompensated HF, Aronson et al showed BUN was also a predictor of adverse outcomes after discharge, comparing with the impact of serum creatinine. Moreover, BUN had at least equal role in determining prognosis and predicting mortality compared with N-terminal brain precursor natriuretic peptide (NT-proBNP) . In addition, It has been shown that in patients with stable CHF, elevated BUN levels are still strongly associated with short and long-term mortality . The precise mechanisms underlying the relationship between BUN and HF are that in patients with HF, low cardiac output decreases renal blood flow and GFR which leading to an increase of urea and thus BUN. Meanwhile, BUN may also be affected by intestinal function, nutritional status such as protein intake or systemic catabolism, and neurohumoral factors . As expected, our data suggested that patients with heart failure had a higher BUN levels than that in the general population, of note, the positive relationship between BUN and D-dimer remained significant even after adjustment for potential confounding factors, in multivariate linear regression analysis. Although we were unable to elucidate the definite causes for this correlation, inflammation might play a role in this regard. It was proposed that BUN increased levels of inflammatory markers and mediators which leading to hypercoagulability and embolism in alcoholic hepatitis patients .
As we known, D-dimers are fibrin degradation products released into the bloodstream after blood clot fibrinolysis that have classically been used for the evaluation of venous thromboembolism. However, D-dimers are also serum acute-phase proteins (APP) that show upregulated expression after stress, infection, or worsening disease states . Increasing evidences have showed that inflammatory response played an important role in the development of DVT. Acute DVT causes a systemic inflammatory response characterized by elevated inflammatory factors and temporal accumulation of inflammatory cells including white blood cells [43, 44]. Dawei Liu et al studied 1179 patients of tibial plateau fractures, and found that platelet and neutrophil count were independently associated with elevated D-dimer levels . Moreover, data from 84 patients with lung cancer showed the accumulation of massive neutrophils in the inflammation sites leads to embolism and thrombosis which resulting poor prognosis . One reason D-dimers may be predictive of the outcome is because they serve as a biomarker of inflammation. In consistent with this studies, our data suggested that plasma D-dimer levels were significantly positively associated with white blood cell counts, furthermore, white blood cell counts was an independent predictors for a high D-dimer level.
Our study has several limitations, worthwhile mentioning. Firstly, it was a single centre and observational study with a limited number of patients, and our results may not be extended to patients in other regions due to the heterogeneity in individual. Secondly,we only measured D-dimer levels at admission, and it was therefore not possible to assess changes in D-dimer levels over time and to evaluate the implications of these changes on CHF outcomes. Thirdly, the follow up time was only 2 years, and the more long-term effect of D-dimer on prognosis still needs to be further studied. We're just looking at all causes of death and the exact cause of death was not analyzed. Last but not least, due to the observational study design, the effect of unmeasured confounders may have impacted the results, although we performed statistical adjustments. Despite these limitations, our results still have a potential clinical significance and merit further researches, particularly for elderly patients with end-stage heart failure.