The associations between the prevalence or prognosis of HF and MetS have been shown in many studies.8–11 However, most of these studies were cross-sectional in design, which prevents drawing causal inferences, and only a few longitudinal studies have been reported. A longitudinal study with 2314 middle-aged men reported that MetS was a significant risk factor for HF, with an HR (95% CI) of 1.80 (1.11 to 2.91).16 A study of elderly individuals in their seventies reported that MetS increased the occurrence of HF, with an HR (95% CI) of 1.49 (1.10-2.00),17 and another study of elderly individuals with a mean age of 69 years also reported that MetS was a predictor of HF with an HR (95% CI) of 1.58 (1.16–2.15).18 In contrast, in a study of participants with a mean age of 62 years old, MetS was not a significant risk factor for HF.13 The present study was a large population-based study that included over 2 million individuals in their fifties. MetS was a significant risk factor for HF, and the HR in men was similar to that reported in a study of middle-aged men.16 Although the results of studies in elderly populations were inconsistent, the HR in the present study was higher than that in a study conducted with elderly participants in which MetS was reported to be a significant risk factor for HF.17, 18
The present study revealed that the effect of MetS on HF differs by sex. The HR (95% CI) in men was 1.711 (1.433–2.044) and that in women was 2.144 (1.674–2.747), showing a higher risk of MetS associated with HF in women than in men. To the best of our knowledge, this is the first study to demonstrate the sex difference of MetS as a risk factor for HF.
In this study, we considered the known risk factors for HF as covariates for adjustment in the Cox regression analysis. It is well known that AMI is a major risk factor for HF. In the study with a median follow-up time of 3.2 years, 31% of men and 46% of women developed HF among those hospitalized due to AMI.19 Another study reported that approximately 84% of patients with coronary heart disease developed HF during the 19-year follow-up.20 In the present study, AMI increased the risk of HF by 131-fold in men and 83-fold in women, which are considerably higher risks than those previously reported. In the National Health and Nutrition Examination Survey (NHANES) study,20 the relative risk of AMI was 8, and in the Framingham study,21 the HR was 6. The reason that the HR of AMI was extremely high in our study was thought to be that as the study population was composed of relatively healthy individuals and patients with a history of cardiocerebral vascular diseases were excluded; additionally, the follow-up period was relatively short compared to that of the NHANES study or Framingham study. Namely, in subjects who do not have underlying disease that can lead to HF, the effect of AMI on the occurrence of HF within a short period is suspected to be critical. The HR of AMI for HF was higher in men than in women, which coincided with the findings of a previous report.20
The association between BMI and HF exhibited obvious sex differences. In women, BMI of 23.0-29.9 kg/m2 increased the risk of HF by 1.2- to 1.3-fold, and obesity (BMI ≥ 30 kg/m2) increased it by 2.1-fold, whereas in men, overweight was not a significant risk factor for HF. This result is consistent with many studies that reported that overweight increased the HF risk in women more significantly than in men.20, 22–24 In the present study, underweight (BMI < 18.5 kg/m2) increased the risk of HF in both men and women. Although various studies reported the association between BMI and HF, underweight has rarely been separately evaluated.25–27 The increased risk of HF by underweight is supported by a recent study that reported associations among obesity degree, glycemic status, and risk of HF.28
In this study, low hemoglobin was a risk factor for HF; however, high hemoglobin levels were not a risk factor despite the significantly high prevalence of HF in the high hemoglobin level population. Low hemoglobin levels and lower blood viscosity, hypoxia and enhanced nitric oxide (NO) activity induce reduced vascular resistance, followed by increased cardiac output. Increased cardiac output leads to left ventricular hypertrophy and cardiac enlargement, which can eventually lead to HF.29 Different results have been reported regarding the association between HF and hemoglobin level; while Klip et al.30 reported that both low levels and high levels of hemoglobin increased the risk of HF compared to the risk associated with normal hemoglobin levels, Coglianese et al.31 reported that high and normal hematocrit levels were associated with a higher risk of HF than low hematocrit levels. These reports explained that a high level of hemoglobin increases vascular resistance by scavenging nitric oxide, a vasodilator, with induces hypertension, left ventricular hypertrophy and finally HF. These different associations between hemoglobin level and HF risk are suspected to result from the different follow-up periods and different study populations. While the follow-up period of our study was relatively short, with a maximum of 8 years, the study of hematocrit and HF31 was performed over 20 years, and the study of hemoglobin and HF had a follow-up of a median of 6 years.30 Additionally, while our study was performed in a healthy population without underlying cardiovascular disease, which is closely related to HF, the study of hemoglobin and HF30 did not exclude the population with those underlying diseases.
Despite the positive aspects of the present study, there were some limitations that should be addressed. First, this study evaluated the subjects’ metabolic status based on data from 2009. Even if a subject who had been classified into the normal group on the basis of the data from 2009 developed MetS during the follow-up period, the subject was analyzed in the normal group. Although the number of subjects whose metabolic status was changed may not be substantial considering the total study population, there can be an effect on the accuracy of the results. Second, our study excluded subjects with a history of malignancy or cardiocerebral vascular disease; thus, the association between MetS status and HF risk was analyzed in a relatively healthy population, which means that this result may not be generalizable to high-risk populations.