In this meta-analysis, by pooling the results of all available prospective cohort studies, we found that subjects with presence of OH were associated with about 30% higher risk of CHF incidence compared with those without OH at baseline. We also found that association between OH and increased CHF risk seemed to be significant in middle-age participants, and in those with hypertension or DM, but not significant in the elderly subjects, or in those without hypertension or DM. These results confirmed the hypothesis that individuals with OH, even without other CVD or risk factors, are at high risk for development of CHF in the future.
Although several previous cross-sectional studies have shown that presence of OH is independently related to left ventricular hypertrophy confirmed by electrocardiogram or echocardiography 
, the exact mechanisms underlying the significant predictive effect of OH for development of CHF are not known. Besides, at this stage, we can’t decide whether or not OH was causally related to CHF and whether or not OH was only a marker of a generally increased risk of CHF incidence. Several suggested mechanisms may be helpful to understand the relationship between presence of OH and increased risk for future CHF, of which autonomic dysfunction is an interesting one. It has been well recognized that baroreflex dysfunction probably induced by impairment of baroreceptor due to aging or atherosclerosis, is one of the most important causes of OH 
. Indeed, when subjects stand up from a supine position, blunted baroreceptor may fail to deactivate the baroreflex and the vagal output therefore can not be down-regulated, leading to OH 
. On the other side, dysfunction of baroreflex has also been observed in CHF patients 
. Impaired baroreceptor may fail to activate the baroreflex in CHF patients with hemodynamic stress, and the sympathetic tone maintained activation, which has been accepted as an important mechanism underlying the pathogenesis and progression of CHF 
. Furthermore, increasing studies in both animal models 
and human patients 
suggested that activation of baroreflex with an implanted device may be a potential treatment for CHF, reflecting the fact that dysregulation of baroreflex may be an intermediate process for the association between OH and incident CHF. In addition to autonomic dysfunction, some other mechanisms have also been suggested to be involved, such as reduced coronary flow caused by frequent postural BP drop 
, increased early subclinical atherosclerotic burden 
, abnormal nocturnal change in BP 
, and increased longstanding cardiovascular overload 
. These mechanisms are also needed to be confirmed by future studies.
Our stratified analysis indicated that the significant association between OH and CHF incidence can be found in middle-age subjects and those with hypertension and DM at baseline. These results highlight the predictive effect of OH for future CHF in both the low-risk population and the high-risk population with known CHF risks. Although the results were not significant for elderly subjects and those without hypertension or DM, our study still found presence of OH increased the risk of future CHF in these subgroups (HRs all >1). In our point of view, these insignificant results may be attributed to the small number of the included studies.
Our study has some limitations which should be considered when interpreting the results. First, the number of studies included in the meta-analysis and stratifies analyses is small. The results for some subgroups should be interpreted with caution. Second, the CHF outcomes of the included studies were defined as CHF hospitalization or death. So, some less severe or asymptomatic CHF cases may not be included. Third, our meta-analysis is based on observational studies. Hence, we cannot exclude the chance, residual or unmeasured confounding. However, since there seemed to be no evidence-based effective intervention for the treatment of OH 
, it is difficult to confirm our results in a large randomized trial. Fourth, potential therapy to OH and many kinds of medications such as antihypertensive medication may affect the risk between OH and CHF. However, as indicated in a recent review 
, many commonly recommended interventions for OH have a limited evidence base supporting their use, and the effects have not been confirmed. Also, effects of some antihypertensive medications on OH, such as angiotensin-converting enzyme inhibitors, are not always consistent 
. Furthermore, potential treatment for OH was not specified in the included studies, although the use of antihypertensive medications was adjusted in two of the studies when estimating the association between OH and incident CHF 
. We acknowledged that lack of controlling for potential treatment to OH and other medications is an important limitation of our study. Fifth, we did not have data on individual studies to assess CHF etiology (ischemic or non-ischemic) or types (preserved or reduced left ventricular systolic function). Nevertheless, our study also has numerous strengths, including the relative high quality of studies included (quality score ranging from 7 to 9), a large pooled sample size, robustness of the results in sensitivity analysis, and use trim-and-till analysis to handle potential publication bias.
In conclusion, results of our meta-analysis confirmed that presence of OH is related to a significant increased risk for development of CHF in the future, especially for the middle-age subjects and those with morbidities such as hypertension and DM. Studies are needed to explore the potential mechanisms underlying this association. More importantly, screen for OH may be of great clinical significance for the early identification of subjects at higher risk for development of CHF.