Causal effects of heart rate variability on hypertension: A Mendelian Randomization study

Hypertension is an important risk factor for developing several health disorders, such as cardiovascular disease, brain, or kidney conditions (1). It has been shown that a low heart rate variability (HRV) is associated with hypertension (2), but it is uncertain whether this association reflects a causal relationship. Therefore, the aim of the current project is to strengthen the evidence for a causal relationship. Hypertension is defined by the World Health Organization (WHO) as a condition in which the pressure in the blood vessels is persistently raised (1). It is one of the leading causes of Disability Adjusted Life Years (DALYs), and it increases the risk of heart, brain, kidney, and amongst other diseases (3). In 2010, 1.4 billion people globally are estimated to have been suffering from the condition (4). This number is expected to rise to 1.56 billion by 2025, which amounts to 29% of the adult population (3). Additionally, in 2016 44% of all noncommunicable disease-related deaths were due to cardiovascular deaths, of which hypertension is the most important risk factor (4). Hypertension is caused by the influence of multiple genes, environmental risk factors, such as diet and alcohol intake and their interaction (5). Another factor associated with hypertension is the functioning of the autonomic nervous system (6). 
A relatively easy, non-invasive tool to assess cardiac autonomic activity is heart rate variability (HRV)(7). HRV reflects the variation in time between consecutive heartbeats. It is controlled by the autonomic nervous system, consisting of the parasympathetic and the sympathetic branches, through which the heart rate is adjusted in response to several stimuli (8). These stimuli can be internal or external, and physical or emotional. A decreased HRV has been associated with several negative health outcomes, such as diabetes (9), cardiovascular disease (6), and as mentioned before, hypertension (6). The association between HRV and hypertension in the general population has been studied in several cross-sectional and prospective studies (6, 10-11). In the previously mentioned studies, the main relationship studied was the cross-sectional association between HRV and pre-existing hypertension or the development of new-onset hypertension. In the ARIC cohort (6), the researchers found that individuals with hypertension at baseline had a lower HRV compared to those without hypertension. Additionally, they observed that a low HRV predicted hypertension over a follow-up period of nine years. These results are consistent with another study done within the ARIC cohort (11) and the Framingham Heart Study (10), in which autonomic function and reduced vagal function were associated with the development of hypertension. 
Besides these observational studies on the association between HRV and high blood pressure, several studies (12-13) have investigated the genetic correlation between the two variables. Previous twin and family studies (14-15) have shown both are heritable, with the heritability of HRV being estimated between 25 and 70%, and those of systolic and diastolic blood pressure around 50%. This heritability of both HRV and blood pressure, has led to research examining their shared genetic factors. The results so far have been mixed. The Oman family study (12), did not find a significant correlation between blood pressure and HRV, although the authors themselves suggest the study was likely underpowered. On the other hand, a second study (13) done with a larger sample size, did find a significant genetic correlation between the two traits, implying these traits have shared genetic factors. These shared genetic factors might partly explain the negative association between HRV and blood pressure. 
All of the aforementioned studies regarding the association between HRV and hypertension are based on observational data. From such data, it is difficult to draw causal conclusions, due to confounding bias and possible reverse causation. By using the Mendelian Randomization (MR) approach, these biases are minimized, strengthening the evidence for causality. The results of this study will add to the current body of literature, as it is the first study looking into a possible causal relationship between HRV and blood pressure using the MR approach.