Abstract
Background and Objective:
Hypertension (HTN) is associated with worsening clinical outcomes in neurodegenerative diseases. The relationship between HTN and the age of diagnosis (ADx) of Huntington’s Disease (HD) is not clear, however. This study sought to determine if the presence of HTN in adult patients with pre-manifest HD was associated with an earlier ADx compared to normotensive patients with HD.
Methods:
Pre-manifest participants from Enroll-HD were included if they had a CAG of ≥ 36, baseline diagnostic confidence level < 4, baseline total functional capacity score > 11 and baseline motor score < 21. There were 3020 pre-manifest participants with HD and 293 reported a diagnosis of HTN. HTN was transformed into a time-dependent variable, and a Cox proportional hazard survival model determine if the presence of HTN affected the time to motor conversion. Baseline CAG-Age Product (CAP) score, CAG repeat length, baseline age, sex, baseline BMI, smoking history, and region were included as covariates.
Results:
Participants with HTN had an increased annualized hazard of motor conversion compared to normotensive participants with HD [HR=1.29, 95% CI (1.02 – 1.64), p=0.034].
Conclusions:
A previous study reported a protective effect of HTN in HD, but did not account for the fact that the prevalence of HTN increases with age. By controlling for this confounder, we more accurately outline the association between the ADx of HD to demonstrate that a diagnosis of HTN may be associated with an earlier ADx of HD. These results represent an association, however, and further investigation is warranted.
Keywords: Hypertension, Huntington’s Disease, symptom onset, Enroll-HD
INTRODUCTION
Huntington’s Disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HTT gene and is characterized by motor, cognitive, and functional impairments that worsen over time.1, 2 Age of HD Diagnosis (ADx) is considered to be the onset of disease progression and is negatively correlated with CAG repeat length.3 However up to 60% of the variation in the ADx is also affected by genetic and environmental factors.4-7
Hypertension (HTN), defined as a systolic blood pressure ≥ 140 mmHg or a diastolic blood pressure ≥ 90, affects approximately 32%of Americans over the age of 188 with similar estimated world-wide prevalence.9 HTN is known to have detrimental effects on the cardiovascular system; however, the sustained presence of HTN and cardiovascular disease can negatively impact the structure and function of the brain.10-14 Untreated HTN is also thought to increase the risk of developing neurodegenerative diseases, such as Alzheimer’s Disease, and hasten the progression of such diseases.15-18Minimal data exists to document the potential impact of HTN on disease progression in the HD population.
A recent study utilizing the REGISTRY database suggested that a concomitant diagnosis of HTN and HD was associated with a significantly later ADx compared to normotensive patients with HD.19 Unfortunately, this study did not seem to account for the fact that the incidence of HTN increases with age, which could mistakenly demonstrate a protective effect of HTN. Therefore, we leveraged the larger Enroll-HD database to further delineate the association between presence of hypertension and the ADx in HD.
METHODS
Enroll-HD is an international clinical research platform to facilitate research in HD.20 Data sets are collected annually on participants in this multi-center longitudinal observational study. Data are monitored for quality and accuracy using a risk-based monitoring approach. All participating sites are required to obtain (and maintain) local ethics committee approvals. All participants provide signed informed consent for their data to be included. At the time of this analysis (July 18th, 2019), the fourth periodic dataset was the most up-to-date version of available data. This version of the database includes 15,301 participants from over 150 sites across the world and includes participants with pre-motor-manifest HD, motor-manifest HD, genotype-negative participants, family controls and healthy controls. The Enroll database also includes longitudinal data for participants who had previously participated in the REGISTRY study21 and then went on to participate in the Enroll-HD study.
Participant Selection
For the current study, only participants with pre-motor-manifest HD at the time of study entry were included. This included participants with a CAG repeat length of ≥ 36 and a diagnostic confidence level (DCL) of less than four at their baseline visit based on Unified Huntington’s Disease Rating Scale (UHDRS).22 Although there is some inconsistency in terminology, the age at which a participant receives a DCL of four (i.e. when they are “diagnosed”) is often considered the ADx and is assigned only when the clinical rater is at least 99% certain that the individual has motor-manifest HD, based on the presence of clinical motor abnormalities seen on examination. Within the Enroll database, there are some participants with a DCL less than four who have (1) relatively high total motor scores (TMS) or (2) relatively low total functional capacity (TFC) scores. To ensure that all participants included did in fact have pre-manifest HD, only participants with a TMS of ≤ 20 and a TFC score ≥ 11 were included (Figure 1). These 3,020 eligible participants were divided into those with a known diagnosis of HTN and those without a known diagnosis of HTN.
Figure 1. Exclusion Criteria.
CAG: Cytosine-Adenine-Guanine
DCL: Diagnostic Confidence Level
HD: Huntington Disease
HTN: Hypertension
TFC0: Baseline Total Functional Capacity Score
TMS0: Baseline Total Motor Score
HTN Diagnostic Criteria
Participants were classified as hypertensive or not based on available, self-reported comorbidity data and medication data. Additionally, if a participant was taking a medication for which the listed indication within the Enroll dataset was HTN, that participant was included in the HTN group. If the date of diagnosis of HTN did not align with the earliest start date of an anti-hypertensive medication, the earlier date of the two was used to mark the diagnosis of HTN. It is important to note that the Enroll-HD database includes information about age of diagnosis (comorbidity dataset) and age of initiation of medications (medication dataset). This information was used to define the age of hypertension diagnosis.
Statistical Considerations
We performed a Cox Proportional Hazard Regression survival analysis to compare the risk of receiving a motor diagnosis between the HTN and normotensive groups. In this context, “failure time” was considered the age at which the participants received a motor diagnosis. For participants who were not given a motor diagnosis during the Enroll-HD study, their age at their last evaluation was used, and they were noted to have not received a motor diagnosis at the time of their last known visit (i.e., right-censoring). This method was used rather than interval-censoring given relatively inconsistent intervals between visits amongst participants in the Enroll platform. Participants are generally seen on an annual basis, but this can vary widely amongst participants. Importantly, HTN was treated as a time-dependent risk factor meaning that a participant with a new hypertension diagnosis during the study period was only considered to have this risk factor beginning at the time of HTN diagnosis. Alternatively, participants that received an HTN diagnosis prior to the beginning of the study period were considered to have HTN beginning at their baseline study visit. The data were considered left-truncated at the age of each participant’s first observation in the Enroll-HD database so that the risk period analyzed was confined to the interval of study participation and only prospective HD diagnoses were considered.
We included baseline age, CAG repeat length, baseline CAP score, baseline BMI, tobacco use, and region as covariates in this analysis. Ideally, CAP score accounts for age and CAG length. However, we also included the main effects of CAG and age to ensure that the underlying age-genetic relationship is appropriately accounted. This is mathematically equivalent to including the main effects of CAG, age, and the interaction of these two terms. We included tobacco use as a covariate given that this has been shown to be associated with an earlier ADx7, 23 and the known relationship between HTN and tobacco use. Additionally, we included baseline BMI as a covariate in the models as it may be presumed that participants with HTN have a higher BMI. This is also important since increased body weight is associated with slower disease progression in HD. By including these covariates, treating the presence of HTN as a time-dependent risk factor, and employing left-truncation, we have adjusted for potential confounders.
We were interested in exploring how the use of antihypertensives may affect the ADx of HD. To do this, we looked only at the participants with HTN, specifically, focusing on those participants who received a HTN diagnosis prior to receiving a motor diagnosis of HD. This group of participants was split into groups of those who were being treated with an antihypertensive and those that were not. We performed a Cox Regression analysis that differed from the analysis previously described. Because all participants had HTN in this secondary analysis, we did not treat medication use as a time-dependent variable. Furthermore, we investigated the risk of receiving a motor diagnosis of HD per year in the Enroll study between the treated and untreated hypertensive participants. The same covariates as described above were included in the model.
For all analyses, a p-value of <0.05 was considered significant. RStudio was used to perform all statistical analyses.
RESULTS
As noted above, there were statistically significant differences between the normotensive group (n=2727) and the HTN group (n=293) in terms of CAG repeat length, baseline age, and baseline CAP score. There were no significant differences between groups related to sex or historical tobacco use (Table 1). For the primary analysis, participants with HTN had a significantly increased annualized hazard of receiving a motor diagnosis (Hazard Ratio = 1.29, 95% Confidence Interval [1.02 – 1.64], p=0.034) (Table 2, Figure 2). The median ADx of participants with HTN was approximately two years earlier than participants in the normotensive group. Within the study period, 121 of the 293 (41%) of the participants with HTN group received a motor diagnosis compared to 661 of 1295 (24%) participants in the normotensive group. Of the 293 participants with HTN, 176 of them received this diagnosis prior to their baseline visit. Of those participants, the mean number of years that they had already had HTN prior to their first visit day was 7.90 years (S.D. 6.74). The mean age of diagnosis of HTN was 46.16 years (S.D. 12.12).
Table 1:
Baseline Characteristics
| HTN Group | Normotensive Group |
p-value | |
|---|---|---|---|
| N | 293 | 2727 | |
| Female, n (%) | 86 (61.9) | 758 (58.5) | 0.447 |
| Baseline Age, mean ± S.D. | 49.34 ± 12.05 | 38.23 ± 11.34 | <0.0001 |
| CAG, mean ± S.D. | 41.14 ± 2.24 | 42.72 ± 2.89 | <0.0001 |
| Baseline CAP Score, mean ± S.D. | 353.54 ± 85.74 | 330.44 ± 95.51 | <0.0001 |
| BMI, mean ± S.D. | 29.31 ± 5.90 | 25.74 ± 5.16 | <0.0001 |
| History of tobacco use, n (%) | 68 (48.9) | 679 (52.4) | 0.431 |
| Region, n (%) | 0.907 | ||
| Europe | 190 (64.8) | 1758 (64.5) | |
| Northern America | 88 (30.0) | 827 (30.3) | |
| Australia/Asia | 15 (5.1) | 137 (5.0) | |
| Latin America | 0 (0.0) | 5 (0.2) |
BMI: Body Mass Index
CAG: Cytosine-Adenine Guanine
CAP Score: CAG-Age Product Score [age * (CAG-33.66)]
S.D.: Standard Deviation
Table 2:
Effect of covariates on the ADx of HD within the model
| Hazard Ratio | 95% CI | p-value | |
|---|---|---|---|
| HTN | 1.29 | 1.02 – 1.64 | 0.034 |
| Baseline CAP Score | 1.01 | 1.005 – 1.009 | <0.0001 |
| Baseline Age, years | 0.96 | 0.93 – 0.99 | 0.039 |
| CAG Repeats | 1.07 | 0.98 – 1.16 | 0.119 |
| Baseline BMI, kg/m2 | 0.99 | 0.97 – 1.00 | 0.087 |
| Sex* | 1.19 | 1.02 – 1.37 | 0.022 |
| History of tobacco use | 1.06 | 0.92 – 1.22 | 0.439 |
| Region^ | |||
| Europe | 3.09 | 1.77 – 5.38 | <0.0001 |
| Latin America | 14.11 | 1.81 – 110.00 | 0.012 |
| Northern America | 2.20 | 1.24 – 3.89 | 0.007 |
Relative to females
Relative to participants from Australia/Asia
BMI: Body Mass Index
CAG: Cytosine-Adenine Guanine
CAP Score: CAG-Age Product Score [age * (CAG-33.66)]
Figure 2. Probability of Receiving a Motor Diagnosis Based on the Presence of Hypertension.
The survival curve was generated by fixing covariates so that the curve represents male participants from North America with a history of tobacco use, a CAG repeat of 42, baseline age of 40, and baseline BMI of 26. The baseline CAP score was set at 333 based on the chosen CAG and baseline age.
For the post-hoc analysis, there were 255 participants that received their diagnosis of HTN prior to receiving a motor diagnosis of HD or prior to the time of censoring. Of these 255 participants, 26 were not being treated for their hypertension prior to their reported ADx of HD. Their baseline demographics are described in Table 3. The treated group was significantly older compared to the non-treated group, but had a significantly lower CAG repeat length. The baseline CAP score between groups, consequently, did not differ significantly. The participants being treated had a significantly lower annualized risk of receiving a motor diagnosis of HD (Hazard Ratio = 0.48, 95% Confidence Interval [0.24 – 0.99], p=0.0457) (Supplemental Figure 1). Treatment regimens varied greatly, but the most commonly used medications were angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), with 165 of the treated participants using one of these medications (supplemental Table 1).
Table 3:
Demographics Between Participants with HTN Being Treated with an Anti-Hypertensive and Those Not Being Treated
| Treated Group | Non-Treated Group |
p-value | |
|---|---|---|---|
| N | 26 | 229 | |
| Female, n (%) | 126 (55.0) | 14 (53.8) | 0.909 |
| Baseline Age, mean ± S.D. | 50.34 ± 12.03 | 43.04 ± 10.06 | 0.003 |
| CAG, mean ± S.D. | 40.88 ± 1.90 | 41.88 ± 2.42 | 0.014 |
| Baseline CAP Score, mean ± S.D. | 351.00 ± 85.30 | 338.63 ± 82.23 | 0.483 |
| BMI, mean ± S.D. | 28.98 ± 5.48 | 29.29 ± 5.44 | 0.786 |
| History of tobacco use, n (%) | 111 (48.5) | 14 (53.8) | 0.603 |
BMI: Body Mass Index
CAG: Cytosine-Adenine Guanine
CAP Score: CAG-Age Product Score [age * (CAG-33.66)]
S.D.: Standard Deviation
Amongst the 255 participants described above, we also performed a sensitivity analysis aimed at investigating if the age of HTN diagnosis had an effect on the ADx of HD. The reason for this analysis was to test the hypothesis that those participants who were diagnosed earlier in life would have longer-standing HTN with a subsequently higher annualized risk of receiving a motor diagnosis of HD. We chose the age of HTN diagnosis as our predictor variable instead of years of HTN because of the assumption that those with long-standing HTN may just be older and closer to their ADx. We found that an older age of HTN diagnosis was associated with a significantly lower annualized hazard of receiving a motor diagnosis of HD, consistent with our a priori hypothesis (HR = 0.95, 95% CI [0.92 – 0.98], p<0.001).
The above-mentioned analyses were performed based on the assumption that treating the diagnosis of HTN as a time-dependent covariate was important. To ensure that this assumption was accurate, we analyzed the Enroll dataset using similar methods as described in the previous report in an effort to replicate those results.19 Additionally, we repeated our primary analysis but did not include age as a covariate and did not treat the diagnosis of HTN as a time-dependent covariate. In both instances, we spuriously induced a significant protective effect of HTN in HD. The methods and results of these analyses are outlined in the supplemental material. The results from these analyses demonstrate the importance of treating HTN as an age-dependent factor and that not doing so may spuriously induce findings suggestive of a protective effect of HTN in HD.
DISCUSSION
In this study, we demonstrate that a concomitant diagnosis of HTN amongst participants with the HD gene expansion is associated with a significantly earlier ADx compared to normotensive participants with the HD gene expansion. Additionally, we provide very preliminary evidence demonstrating that participants with HTN who were being treated with an anti-hypertensive had a significantly lower annualized risk of receiving a motor diagnosis of HD. We also demonstrate that an earlier age of diagnosis of HTN is associated with a significantly increased annualized risk of receiving a motor diagnosis of HD. These findings may point to an important link between blood pressure control and the rapidity of HD progression. Furthermore, these results may provide preliminary evidence that surveillance and maintenance of cardiovascular health in HD might provide an opportunity to delay onset and slow disease progression. However, additional clinical validation and mechanistic research is required to support this claim.
These findings do contradict a recently published study that queried the role of blood pressure on the ADx of HD and suggested that the presence of HTN was associated with a later ADx, thus implying a protective effect of HTN in HD.19 The authors of that study noted that their findings may have been influenced by the fact that the prevalence of HTN increases with age. We have addressed that possibility and uncovered an opposite effect of HTN on the ADx. Treating HTN as a time-dependent risk factor is critical in this analysis, given that the risk of developing both HD and HTN increases with age.24 Failure to account for this automatically leads to a spurious negative association and could account for the discrepancies between the current and previous analysis of HTN in HD. In fact, we employed the same methods used in the previous study and replicated those results.19 Additionally, we repeated our survival analysis but did not control for age and did not treat HTN as a time-dependent covariate, which resulted in findings suggestive of a protective effect of HTN in HD. These analyses demonstrate the importance of accounting for the fact that the risk of developing HTN increases with age, as we have done. Those who experience HTN prior to HD diagnosis inherently tend to have later HD diagnosis, independent of any physiological effect of HTN. By definition, they have had more time to develop HTN while still pre-HD. The definition of the putative risk factor inevitably leads to later diagnostic age. Further, the later age at diagnosis is associated with shorter CAG repeat lengths. The situation is exacerbated by the necessary exclusion of those who received a motor diagnosis of HD prior to study entry. These considerations were reflected in the baseline differences in age and CAG length (Table 1), and these discrepancies highlight the need for careful statistical adjustment.
False risk/protective association are removed if we explicitly consider the ages of HTN as well as HD diagnoses, assume that HTN can only have an effect after it occurs (time-dependency), and control for CAG repeat length— a well-known age-dependent etiological HD factor. Finally, we should recognize that the available data limits valid analysis to events during prospective observation (left-truncation).
Limitations of the study include the possibility of recall bias. Participant diagnosis of hypertension and onset of hypertension diagnosis are dependent on information obtained from participants or their loved ones – not medical chart abstraction or clinical report. It appears that the HD population may be more likely to underreport than over-report a diagnosis of HTN. Compared to a world-wide prevalence of approximately 31%, the prevalence of reported HTN was approximately 10% (293/3020) among those in the Enroll-HD sample who had the HD gene expansion. It is therefore possible that HTN was substantially under-reported in the preHD group at risk. If this is so, we believe the most likely consequence is a bias towards the null hypothesis of no association between HTN and ADx. We have found the opposite, despite this potential bias. Related to this, another limitation is the possibility that receiving a diagnosis of HTN may be the result of increased healthcare utilization. This is important in the setting of HD where patients who are beginning to have early manifestations of HD may be more likely to seek out medical care. In doing so, they may increase their likelihood of receiving a diagnosis of HTN as they are nearing their predicted ADx. Consequently, the participants receiving a diagnosis of HTN may simply be those who are closer to their predicted onset. By controlling for CAP score and baseline age and CAG, we have attempted to account for this possible confounder. Another potential limitation related to the reporting of the presence of HTN is that the reported age of diagnosis of HTN may not be indicative of when the disease process started. Many participants may be clinically hypertensive for many months or years prior to receiving a formal diagnosis of HTN, which would again alter the time-dependent aspect of this study. Unfortunately, the Enroll-HD database does not contain vital sign data. Due to lack of vital sign data, it is also unclear which of the participants with HTN subsequently achieved well-controlled blood pressure. Medication records indicate that most participants were treated with an anti-hypertensive, but the treatment efficacy is unknown. Thus, we can only speculate that blood pressure control may be beneficial in the slowing of HD. To the best of our knowledge, there is currently no human data describing the effect of antihypertensives on the ADx of HD. However, a recent study did report that the use of felodipine in mice may induce autophagy and provide benefit for neurodegenerative diseases, including HD, but these benefits were independent of the cardiovascular system.25 Our post-hoc analysis demonstrated that the use of an antihypertensive agent in participants with the HD gene expansion who do not have HTN does not significantly alter the annualized risk of receiving a motor diagnosis. This additional information helps increase our confidence that our results are being driven primarily by the presence of HTN rather than the use of antihypertensives for the treatment of HTN.
Despite these weaknesses, there are multiple strengths of this study. First and foremost, we have employed statistical techniques to treat the presence of HTN as a time-dependent risk factor. We were also able to utilize longitudinal data from Enroll-HD. The Enroll-HD database represents the largest database of patients with HD in the world. The number of patients available for analysis, as well as the diversity of participants from around the world, increased the external validity of these results.
Our analyses indicate that the presence of HTN in people with the HD gene expansion is associated with earlier age of clinically significant manifest HD. It is important to note that these findings represent an association between the presence of HTN and the ADx of HD but not necessarily a causative effect. Further studies are needed to investigate the potential causal link between the two. In any case, this data contradicts any notion that the presence and perhaps the suboptimal treatment of HTN leads to beneficial effects in HD.
Supplementary Material
Supplemental Figure 1 Probability of Receiving a Motor Diagnosis by Treatment Status of HTN Amongst Participants with HTN
The survival curve was generated by fixing covariates so that the curve represents male participants from North America with a history of tobacco use, a CAG repeat of 42, baseline age of 40, and baseline BMI of 26. The baseline CAP score was set at 333 based on the chosen CAG and baseline age. Participants with HTN who were being treated with an anti-hypertensive had a significantly lower annualized hazard of receiving a motor diagnosis of HD compared to participants with HTN who were not being treated with an anti-hypertensive.
ACKNOWLEDGMENTS
Enroll-HD is a longitudinal observational study for Huntington’s disease families intended to accelerate progress towards therapeutics; it is sponsored by CHDI Foundation, a nonprofit biomedical research organization exclusively dedicated to developing therapeutics for HD. Enroll-HD would not be possible without the vital contribution of the research participants and their families.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Figure 1 Probability of Receiving a Motor Diagnosis by Treatment Status of HTN Amongst Participants with HTN
The survival curve was generated by fixing covariates so that the curve represents male participants from North America with a history of tobacco use, a CAG repeat of 42, baseline age of 40, and baseline BMI of 26. The baseline CAP score was set at 333 based on the chosen CAG and baseline age. Participants with HTN who were being treated with an anti-hypertensive had a significantly lower annualized hazard of receiving a motor diagnosis of HD compared to participants with HTN who were not being treated with an anti-hypertensive.