3.4 Relationship between survival and the level of RDW and LVMI in HCM patients
According to whether RDW>0.13 and LVMI>181g/m2, the patients were divided into 3 groups, including group 1 (RDW≦0.13 and LVMI≦181g/m2), group 2 (RDW>0.13 or LVMI>181g/m2) and group 3 (RDW>0.13 and LVMI>181g/m2). The results showed that there were statistically different in the occurrence of all-cause mortality and MACE among the groups.(Table 4).Kaplan-Meier analysis showed that the survival rate of group 1 was significantly higher than that of group 2 and group 3 (98.36% vs. 92.86 vs. 54.55%, P=0.000), as shown in Fig. 2a . Besides, the MACE-free survival rate of group 1 was significantly higher than that of group 2 and group 3 (86.89 vs. 62.50 vs. 15.15%, P =0.000) as shown in Fig. 2b .
Discussion
Herein, we determined that a higher baseline RDW was independently associated with the risk of cardiac death, heart failure, and all-cause mortality in a population of HCM patients with RDW values that largely fell within the normal range. In addition, we detected a significant correlation between LVMI and RDW, and we determined that the simultaneous evaluation of both RDW and LVMI was better able to predict adverse events in HCM patients than the evaluation of RDW alone. LV hypertrophy is thus closely associated with high rates of heart failure and mortality among individuals with HCM.
A range of different laboratory parameters have been highlighted as putative markers of inflammation and cardiovascular disease in recent years. For example, uric acid [24], NT-proBNP [25], and troponin [26] have all been previously associated with adverse HCM patient outcomes. Herein, we found higher RDW values to be linked to increases in NT-proBNP and CRP but to decreases in hemoglobin and serum albumin levels, consistent with a higher RDW being indicative of sicker patients. Even after adjusting for a range of potential confounding variables, we found that higher RDW values remained linked to negative outcomes in these HCM patients, underscoring the prognostic utility of this hemodynamic parameter. Importantly, RDW values can be easily established based on the results of a patient’s complete blood count, and thus require no additional medical testing. We also found that the combined evaluation of RDW and LVMI was able to better predict long-term cardiovascular outcomes in HCM patients, indicating that these two predictors may be ideal targets for efforts to better prevent, manage, and treat this dangerous condition.
We found that higher RDW values were linked to clinically significant increases in HCM patient risk of mortality, thus expanding on the results of two prior studies. In a preclinical study, Stanzani et al. had demonstrated that an increase in RDW was independently predictive of increased cardiac mortality in HCM model cats [27]. A separate study of 98 HCM patients with no history of heart failure found RDW to be independently linked to heart failure onset. In this study, we analyzed HCM patients with and without anemia and/or heart failure, and we did not specifically restrict our outcome measurements to heart failure incidence. By expanding the scope of our analyses, we were thereby able to establish RDW as a powerful independent predictor of diverse negative clinical outcomes in HCM patients.
While the mechanistic link between increased RDW values and negative HCM patient outcomes remains to be clarified, there are linked several factors contributing to this relationship. For one, increases in RDW may correspond to folate or vitamin B12 deficiencies [28]. RDW values for most patients in the present study, however, were within the normal range, and we adjusted results for mean corpuscular volume which is correlated with folate and vitamin B12 levels. As such, while we did not directly evaluate patient nutritional status, our results are not consistent with such a model. Second, thrombosis may contribute to the relationship between HCM and RDW given that declining RBC functionality has been previously linked to an increased risk of RBC adherence to endothelial cells and consequent thrombus formation [29]. RDW has reportedly been linked to prothrombotic activity through renin-angiotensin system (RAS) activation through angiotensin II type 1a receptor [22]. Such increases in RAS activating can in turn drive cellular proliferation and hypertrophy, impacting LV hypertrophy and remodeling and thereby contributing to negative outcomes [19]. Third, inflammatory cytokine production may further explain the relationship between RDW and HCM patient outcomes, given the well-documented importance of these cytokines in the context of HCM pathogenesis. Such proinflammatory factors can suppress erythropoietin-induced erythrocyte maturation, which can be partially reflected by a rise in RDW. As such, higher RDW values may reflect increases in underlying inflammation that are associated with poor clinical outcomes [30]. This may thus represent a key mechanism linking high RDW and high rates of negative clinical outcomes in individuals with HCM. There is also a purported link between RDW and abnormal renal functionality [31], although we detected no association between this hemodynamic parameter and serum creatinine levels. Overall, we hypothesize that increases in RDW may correspond to more severe inflammation and risk of thrombosis, thus contributing to a poor HCM patient prognosis. However, future work will be needed to formally test this hypothesis and to more firmly establish the determinants of RDW in those with HCM.
Left ventricular hypertrophy (LVH) is a potential consequence of cardiovascular disease that has been independently linked to SCD risk in individuals diagnosed with HCM. Prior work suggests that RDW is closely linked to specific echocardiographic parameters used to assess LVH in patients with essential hypertension [32], chronic kidney disease [33], and atrial fibrillation [34]. Similarly, we identified a positive relationship between LVMI and RDW in individuals with HCM, indicating that RDW may be a biomarker of LVH. Oxidative stress may explain the relationship between these two variables, as Cave et al. [35] previously showed that angiotensin II, endothelin-1, tumor necrosis factor (TNF), and pulsatile mechanical stretch were able to promote symptoms of cardiac hypertrophy in vitro that were linked to intracellular reactive oxygen species production. Antioxidants can inhibit these pathogenic processes, and depleting endogenous antioxidants can result in an increased RDW [35].
Our article has several strengths. For one, this study was the first to evaluate overall adverse clinical outcomes in HCM patients, with these outcomes having been assessed based on predefined criteria without knowledge regarding patient RDW levels. However, there are also certain limitations to this approach. For one, we are unable to exclude the potential for residual confounding variables having impacted our analysis given that this study was observational in nature. Even so, we hypothesized the existence of a relationship between RDW levels and adverse outcomes prior to beginning our analyses, thus reducing the risk of erroneous conclusions. We additionally adjusted our analyses for potential confounding variables including clinical and laboratory parameters that were linked to RDW levels in our patient cohort. This study is also limited by the fact that it was a single-center analysis of Chinese patients with HCM previously diagnosed at the First Affiliated Hospital of Sun Yat-sen University during a specific period of time, and so these results may not be generalizable to the general population or to other ethnic groups. We also observed a lower rate of family history of HCM in our patient cohort relative to previously reported rates in epidemiological studies of HCM, which may be attributable to the majority of these HCM patients exhibiting an asymptomatic presentation and not having undergone routine physical examinations in the hospital, thus preventing them from providing a detailed family history. Our study also did not provide any evidence regarding specific clinical approaches that can be taken following the detection of HCM patients with high RDW levels. Additional multicenter randomized controlled trials and genetic studies will thus be essential in order to more fully understand the mechanistic basis for HCM and to identify appropriate approaches that can be taken to treat or manage HCM patients with high RDW.