Baseline characteristics in heart failure
HF severity was assessed using BNP and NHYA evaluations. No significant differences were observed between patients with and without MACE in both the elevated and the preserved CAVI groups. However, compared with those of previous studies, the subjects of this study had higher proportions of patients with NHYA III and higher BNP values, indicating that patients with more severe HF have been included [26, 27]. Additionally, no significant differences in CS classification and HFpEF proportions were observed, and the type of HF was similar between MACE and non-MACE. In the CS classification, approximately half of the study subjects were CS1; less than half of the study subjects were CS2, and the rest were CS3. HFpEF accounted for less than half of the study subjects. These findings were similar to those of previous studies [26, 28].
Blood pressure and MACE
In this study, no difference in BP was observed between patients with and without MACE in the elevated CAVI group; however, the diastolic and mean BPs of patients with MACE were significantly lower in patients with MACE than in those without MACE in the preserved CAVI group. Additionally, the CAVI of patients with MACE was slightly elevated compared with that of patients without MACE (no significant difference), which may reflect arteriosclerosis. In-hospital BPV of patients with MACE was significantly higher than that of patients without MACE in the elevated CAVI group. BPV has been reported not only to increase the risk of cardiovascular complications, including HF, in hypertension [29] but also to increase cardiovascular complication risk in diabetes mellitus [30]. BPV has short-term (variability during all day), medium-term (daily variability), and long-term (visit-to-visit) values, and these reports evaluated visit-to-visit BPV. It has recently been reported that visit-to-visit BPV is also associated with the prognosis of HF [31–33]. In HFrEF, it has been reported that the prognosis worsens, regardless of the size of the variability; however, an increase in the variability range generally causes a poor prognosis [34]. In contrast, in-hospital BPV is associated with the prognosis of arteriosclerotic diseases, such as coronary artery disease and peripheral artery disease [14, 15]. This result was also the case after coronary artery bypass grafting for coronary artery disease [35]. In this study, in-hospital BPV was associated with the prognosis of HF in the elevated CAVI group. Patients with HF who have advanced arteriosclerosis may benefit from the evaluation of in-hospital BPV.
Factors associated with the occurrence of MACE
In both groups, the BMI was significantly low in those with MACE. The OBESICA study in Japan showed that low BMI is associated with poor prognosis in HF [36]. Furthermore, in Japan, the JCARE-CRAD registry has reported similar results [37]. Therefore, this result was similar to those of previous studies. However, in the elevated and preserved CAVI groups, no significant difference in eGFR was observed between patients with and without MACE, and the effect of renal function on anemia was limited. Usually, the left ventricle dilates as HF progresses. Generally, MACE increase with the progression of HF [38], and the results of this study are contradictory. The number of subjects was considered the most important factor in this result, and the left ventricle cavity was excluded in the multivariate analysis. The use of therapeutic medications, the so-called cardioprotective medications, which have been shown to improve the prognosis of HF, was evaluated; however, no significant difference was observed between the groups. Compared with previous studies, the introduction rate for each medication was higher in all groups, which may have been one factor. Moreover, the use of anti-anemic medications was so small that it could not be evaluated in this study.
Impact of Anemia on Heart Failure
Several patients with HF have anemia. Anemia has been reported in one-third to more than half of the Asian patients with HF in the Asian registry (ASIAN-HF trial) in which our hospital also participated [39]. Anemia was reported to be associated with a worsening HF prognosis [7], and similar results were obtained in this study. Additionally, anemia was a factor more related to HF prognosis than BPV. Anemia is often experienced due to decreased renal function caused by HF, also referred to as cardiorenal anemia syndrome. Because this anemia is accompanied by a decrease in erythropoietin production, erythropoiesis-stimulating agents (ESAs) can be expected to improve Hb [40]. However, although ESAs improved Hb, they did not improve HF prognosis [41]. It has also been reported that this result was similar even after using a high dose of ESAs and sufficiently improving anemia [42]. Also, HF is often associated with iron-deficiency (ID) anemia. In the past, many studies have evaluated the effectiveness of iron administration for HF. The improvement in ID with intravenous supplements has been reported to be associated with improved motor performance and quality of life in patients with HFrEF [43, 44]; however, it was not associated with improved prognosis [45, 46]. Anemia may be an important surrogate marker for evaluating HF prognosis. However, as described above, neither ESAs nor iron improves the prognosis of HF; therefore, anemia in HF may be difficult to become a therapeutic target. It has also been reported that hypoxia-inducible factor prolyl hydroxylase, a new medication for treating anemia, improved BNP in patients with HF [47], and these therapeutic medications may provide new perspectives on treating anemia in patients with HF.
Study limitation
The most important study limitation is the number of study subjects. This study was a retrospective, observational, single-center study. The patients were few because vascular function was not evaluated in all patients. In addition to the CAVI, reactive hyperemia, flow-mediated vasodilation, peripheral arterial tonometry, and PWV are known vascular function evaluation methods [48]. However, in this study, only CAVI was evaluated, as the number of subjects for whom examinations other than the CAVI were performed was even smaller.
Although the CAVI has advantages, such as being simpler and less influenced by BP than other methods, one of the limitations was that only the CAVI was evaluated. Additionally, in this study, no patients had autonomic disorder; however, the possibility that underlying diseases and medications affected BPV cannot be denied. Furthermore, the data for this study were extracted from medical charts. Therefore, we could not evaluate the frailty associated with HF prognosis because there was no description of the grip strength or quality of life table/score. The small number of patients with MACE in the preserved CAVI group was also small, and further clinical prospective studies with a larger sample of consecutive subjects whose CAVI was evaluated are needed to confirm the results of this study.