Human T-lymphotropic virus type 1 (HTLV-1) was the first known human retrovirus, described in 1979 by Poiesz.1 It is estimated that 15–20 million people are affected worldwide.2 The incidence of HTLV-1 infection is higher in Japan, Africa, and Caribbean Islands, where it may affect 5% or more of the population.3 The virus was initially associated with adult T-cell leukemia; subsequently, myelopathy (HTLV-1-associated myelopathy/tropical spastic paraparesis – HAM/TSP), uveitis, and infective dermatitis were also associated with the virus.4–7 Only 5–10% of patients, however, develop clinical manifestations.

HAM/TSP is a slowly progressive disease. It is characterized by a chronic spastic paraparesis, neurogenic bladder, neurogenic bowel, spasticity and neuropathic pain. Because these symptoms are similar to those found in patients with other spinal cord diseases (traumatic or non-traumatic), their treatment overlaps, consisting mostly of supportive measures and rehabilitation. There is currently no antiviral treatment for the disease. Once HAM/TSP develops, it is usually progressive and irreversible.

In the past, pulmonary and renal complications were the main causes of morbidity and mortality of patients with traumatic spinal cord injury.8,9 However, cardiovascular disease is now one of the leading causes of death.8,10,11 Risk factors such as diabetes, low HDL-cholesterol (HDL-C), sedentary life-style, and smoking have a higher prevalence among patients with spinal cord injury.8,10,12–14

Few studies describe the cardiovascular involvement related to HTLV-1. In 2014, Layegh et al.,15 in a cross-sectional study assessed atherosclerosis in patients with HTLV-1. The authors found that HTLV -1 infected patients had greater carotid intima-media thickness than age-mached healthy controls. In 1996, Stuver et al. found increased incidence of cardiovascular diseases and EKG changes in patients infected with HTLV-1.16 In 2013, Shabestari et al. found increased prevalence of HTLV-1 among patients undergoing angiography.17

The Human Immunodeficiency Virus (HIV), another retrovirus, is associated to increased cardiovascular risk. Freinberg et al. studied 82,459 patients with HIV during 5.9 years. After adjusting for comorbidities and cardiovascular risk scores, they found that HIV was an independent cardiovascular risk factor, raising the risk of a myocardial infarction by 50%. The mechanism by which HIV increases the risk of myocardial infarction is not known; it is thought that viral induced inflammation and endothelial dysfunction may play a role.18 Anti-retroviral therapies, especially protease inhibitors are also related to higher cardiovascular risk.19 As HIV and HTLV-1 are both retrovirus and share similar replication enzymes such as retroviral proteases,20 one could hypothesize that HTLV-1 infection could also be an independent cardiovascular risk factor.

The objective of the present study was to evaluate the cardiovascular risk profile of patients with HAM/TSP and compare it with the general population.

The social and clinical characteristics of the patients are presented in Table 1. In both groups, 80% of patients were female with a mean age of approximately 51 years (11.3). There was no difference between groups with respect to race (p=0.081). The groups differed in the educational status (p<0.001) and family income (p<0.001), with the control group presenting with more years of formal education and higher income.

The control group had a higher prevalence of hypertension (46% versus 18% of patients in HAM/TSP group, p=0.002). The waist circumference of women of this group was also significantly higher (95cm (13) versus 88cm (13) of HAM/TSP group, p=0.019). The incidence of diabetes mellitus was higher in the HAM/TSP group (16% versus 4% of control group, p=0.026); however, the median fasting blood glucose was similar between the groups (90mg/dl in the HAM/TSP group versus 92mg/dl in the control group, p=0.239). The control group had significantly higher total cholesterol level (200mg/dl (42) versus 179mg/dl (33), p=0.007), and triglyceride levels (median of 134mg/dl versus 102mg/dl in HAM/TSP group, p=0.012, Mann–Whitney). HDL-C level was also higher in HAM/TSP group (46mg/dl (10) versus 39mg/dl (9) p<0.001).

The control group had higher BMI (29kg/m2 (4.7) versus 26kg/m2 (5), p<0.001). The prevalence of obese patients (BMI>30kg/m2) was significantly higher in the control group than in the HAM/TSP group (43% versus 16%, p=0.001). There was no significant difference in the prevalence of metabolic syndrome, although we observed a trend toward higher prevalence in the control group (60% versus 44% of HAM/TSP group, p=0.127).

In the HAM/TSP group, the mean age of onset of myelopathy symptoms was 41 years (12.7). The median FIM scale score was 111 (IQR 109–117). The median provirus load was 2510 HTLV-1copies/105 cells copies/ml (IQR 286–3518). Table 2 shows the characteristics of these patients.

The ASCVD, Framinghan, and SCORE risk scores were calculated for each patient in the HAM/TSP and control groups (Table 3). Both groups had similar ASCVD and SCORE risk scores; however, the control group showed a statistically significant higher Framingham risk score than the HAM/TSP group (median of 7.3% risk of cardiovascular event in 10 years in the control group versus 4.8% in the HAM/TSP group, p=0.024).

Using the ASCVD RISK score, more patients in the control group were found to have an intermediate/high cardiovascular risk than in the HAM/TSP group (43% of patients in the control group versus 23% of patients with HAM/TSP, p=0.037). Similarly, when using Framingham and SCORE, more patients in the control group were classified as intermediate/high risk than in the HAM/TSP group, although this difference was not statistically significant (Table 3).

There was no difference between ultrasensitive CRP and IL-6 in both groups when we used either the absolute value or when the groups were categorized into low and high risk patients according to their lab values (Table 4).

In multivariate analysis, none of the evaluated factors were associated with a better or worse cardiovascular risk profile. Race and income were not included in the model, since race is a variable used in ASCVD RISK. Income showed a strong relationship with education, which could lead to an interaction in the model (Table 5).

Of the 56 patients in this group, 32 were evaluated by the FIM scale. There was no correlation between the FIM scale and the cardiovascular risk of these patients (Table 6).

To our knowledge, this is the first study evaluating the cardiovascular risk profile of patients with HAM/TSP. Although we initially postulated that patients with HAM/TSP could have a worse cardiovascular risk profile than the normal population, this was not seen in our study. In fact, more patients in the control group had higher cardiovascular scores as measured by ASCVD. The median score measured by Framinghan cardiovascular risk score was also higher in this group.

This result can be partially explained by the fact that the prevalence of high blood pressure, total cholesterol, triglycerides, and waist circumference was significantly higher in the control group. However, it is important to note that HAM/TSP patients presented some characteristics that may actually lower their cardiovascular risk, such as low total cholesterol and low blood pressure. Although spinal cord injury patients usually have high prevalence of dyslipidemia, this may not be true for HAM/TSP patients. Doria et al.,33 evaluated 54 HTLV-1 patients for atherosclerosis using carotid artery Doppler. The authors found that only 35% of the patients had atherosclerosis and attributed this fact to the low dyslipidemia prevalence among the studied patients. Furthermore, blood pressure is also an important risk factor for cardiovascular disease and for this reason it is considered in all scores that assess cardiovascular risk. Changes in autonomic control mechanisms were also described in these patients with dysfunction in the sympathetic nervous system. Ohishi et al.,34 showed that HTLV -1 patients had lower average blood pressure in 24h and higher average sleep heart rate when compared to a control group. This study took place in the Japanese city of Nagasaki, and compared 23 HTLV patients with 23 age and sex matched healthy controls. As blood pressure and cholesterol are important cardiovascular risk factors, this can mean that HAM/TSP patients may actually have, in fact, a better cardiovascular risk profile than apparently healthy individuals.35,36

There are other possible explanations for our results, including the application of the cardiovascular scores in the HAM/TSP population. Finnie et al.,10 evaluated the cardiovascular risk of 75 patients with spinal cord injury. Nineteen percent of the patients had an intermediate/high cardiovascular risk when Framingham score was used, against 37% when they evaluated CRP. The authors argued that the Framingham risk score may underestimate the cardiovascular risk of spinal cord injury patients, because it may not consider some specific characteristics of this population. This finding may also be true for the other two scores used in this study.

Another factor that may have played a role in our findings is that the patients in our HAM/TSP group are closely monitored in a specialized rehabilitation center and receive high level medical care. They are evaluated at least annually or semi-annually by a specialized, multidisciplinary medical team, with emphasis not only in rehabilitation, but also in preventive medicine. The fact that these patients had a higher prevalence of history of diabetes than the control group, but their fasting blood glucose levels were similar, demonstrates the close monitoring and control of comorbidities in this group. Considering that they are so strictly monitored, their risk factors may be minimized.

The control group was found to have a higher level of education and family income, which is usually associated with lower cardiovascular risk.37–39 Although one may postulate that if the groups were similar in their social economic status, the difference between the cardiovascular risk could had been even greater (with HAM/TSP patients showing with a more significant lower cardiovascular risk), in our multivariate analysis, education level was not associated with cardiovascular risk.

Despite the fact that HAM/TSP is considered a chronic inflammatory disease, we did not find differences when evaluating ultrasensitive CRP and IL-6 between the groups. About 45% of patients in this study had elevated levels of ultrasensitive CRP, and about 20% had elevated levels of IL-6, with no difference between the HAM/TSP and the control group. Elevated levels of CRP and IL-6 were described by previous studies in HTLV-1 patients.40,41 One possible explanation for our finding is the higher prevalence in the control group of factors also associated to elevated levels of inflammatory markers, such as obesity and hypertension.42,43

The functional capacity of patients with HAM/TSP in this study varied widely, with the score by FIM scale ranging from 72 to 121. A worse functional performance could be related to a higher cardiovascular risk using the hypothesis that most compromised patients are more sedentary.44 However, this study did not demonstrate a positive correlation between cardiovascular risk and the result of the FIM scale.

Our study had limitations. It was a cross sectional study and the number of patients was small. It was designed to detect a difference of 28% prevalence of intermediate/high cardiovascular risk among patients with HAM/TSP and the control group. If the difference between the two groups was smaller than this, we would need a bigger sample size to detect this difference. Although our analysis did not find an important impact of the socio-demographic characteristics on the results, similar baseline characteristics would provide more reliable results. Since we did not evaluate asymptomatic HTLV-1 patients, we can not tell if the results found in the study were due to the myelopathy or to the virus itself.

In this study, the cardiovascular risk profile of patients with HAM/TSP followed in a rehabilitation hospital in Salvador, Brazil was better than the risk profile of the control group of healthy individuals. Further studies are needed to better clarify this issue.

SARAH Network of Rehabilitation Hospitals. The funding source had no involvement during the research and preparation of the article.

The authors declare no conflicts of interest.