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.