ciHHV-6 is a risk factor for angina pectoris

In an article published this month in the Proceedings of the National Academy of Sciences, Louis Flamand, PhD, and team described a relationship between inherited chromosomally integrated HHV-6 (ciHHV-6) and the development of angina pectoris. Inherited ciHHV-6 has been described in the context of heart failure and encephalitis, but this is the first large-scale analysis of disease association with inherited ciHHV-6. The study analyzed DNA from nearly 20,000 individuals between the ages of 40 and 69, of which 0.58% were found to have inherited ciHHV-6. Medical records, hematological, biochemical, anthropometric measurements and telomere lengths were then compared between those with and without inherited ciHHV-6.

Of the 50 diseases monitored, only angina pectoris was significantly elevated at 9.7% (3.3x) in the 113 individuals with inherited ciHHV-6 relative to 19,473 ciHHV-6- control subjects (P = 0.017; 95% CI, 1.73-6.35).

Furthermore, even when adjusted for potential confounding factors (age, body mass index, percent body fat, and systolic blood pressure), the prevalence of angina remained three times greater in iciHHV-6+ subjects (P = 0.015; 95%CI, 1.23-7.15), suggesting that this inherited trait may predispose affected individuals to the development of angina. In addition, the study also demonstrated that inherited ciHHV-6+ individuals with angina have significantly shorter telomeres than age-matched iciHHV-6- subjects (P = 0.006).

Women with ciHHV-6 had a higher prevalence of angina at 14.3% compared to 2.2% of female controls, according to the data in the supplemental tables. Meanwhile, the prevalence of angina in iciHHV-6+ men was 6.3% compared to 4.3% in controls.

The authors propose several potential mechanisms by which ciHHV-6 may contribute to the development of angina pectoris. First, both bacterial and viral infections are thought to play important roles in atherosclerosis development (Chatzidimitriou 2012), and one hypothesis suggests that endothelial cells from ciHHV-6+ subjects activate and produce virions, mRNA, and viral proteins that lead to inflammation as well as immune mediated reactions that can lead to atherosclerotic lesion development. As this virus-mediated inflammatory process continues, and the atherosclerotic lesion grows, the symptoms of angina can appear.

In fact, a recent study has suggested that the reactivation of inherited ciHHV-6 may contribute to heart failure (Kuhl 2014), and the authors of this German study hypothesized that endothelial damage caused by HHV-6 reactivation might explain the observed symptoms of angina as a sequela of myocyte and vascular endothelial dysfunction, which is similar to a mechanism that has been previously reported for parvovirus B19 (Schmidte-Lucke 2010).

Gravel et al. point to the vast body of literature linking short telomere lengths and cardiovascular disease development as an alternative explanation. A recent meta-analysis of 24 studies involving more than 40,000 subjects concluded that telomere length was inversely correlated with the incidence of cardiovascular diseases (Haycock 2014). Considering that the shortest chromosome is responsible for triggering cell damage (senescence or chromosomal instability), and that the chromosome carrying the integrated HHV-6 was the shortest in a preliminary study (Huang 2014), it is possible that angina pectoris could result from an accelerated shortening of the telomere of the chromosome carrying HHV-6 integration. When analyzed for overall length, the telomeres of DNA from ciHHV-6+ subjects were found to be 10% shorter than ciHHV-6− individuals (P = 0.003), therefore substantiating the notion that reduced telomere length is associated with a higher prevalence of cardiovascular disease. The authors propose that the integration of HHV-6 into host DNA may affect the genomic architecture with somewhat unpredictable outcomes.

The German cardiology group that studied ciHHV-6 in cardiac patients found that two-thirds of their 19 ciHHV-6+ patients had mRNA transcripts, indicating active infection. They found that six months of antiviral therapy reduced symptoms of angina, palpitations and dyspnea, but that the symptoms reappeared a year after treatment ended (Kuhl 2014).

A 2012 study by an Italian group found an unusually high level of HHV-6 viremia in coronary atherosclerosis (14.3%) compared to what was found in healthy controls (approximately 2%) using the same assay (Magnoni 2012). They also found elevated levels of HHV-6 viremia in patients with acute myocardial infarction (17.2%) and in patients subjected to heart valve replacement (25%). A German study found that viral persistence in the myocardium correlated with endothelial dysfunction of the coronary microcirculation (Valbrecht 2005). HHV-6 can directly infect vascular endothelial cells, and Caruso et al found that the viral U94/rep gene causes inhibition of angiogenesis, which is essential for wound healing.

Overall, the prevalence of ciHHV-6 in Canada at 0.58% was found to be lower than in the US where it is 0.85% (Hall 2008) but higher than rates found in Japan at 0.2% (Pellett 2012). The highest prevalence reported to date has been in Scotland where the rate is 1.8% (Bell 2014). 41% of the ciHHV-6+ individuals were ciHHV6-A, which is slightly higher than the 33% rate found in the US. The low prevalence of ciHHV6 made it difficult to achieve statistical significance and the authors plan to investigate several disease conditions in further depth.

Interest in ciHHV-6 has grown since it was determined that the integrated virus can activate under certain conditions both in vitro and in vivo (Endo 2014), causing some experts to call for screening of transplant organs and cells. Also, a group at St. Jude Children’s Research Hospital found a possible link between ciHHV-6 and pediatric adrenocortical tumors, where the viral integration occurred in a specific chromosome that is tied to the development of the tumors.


Q: Do you plan any follow-up studies of patients with angina to determine if viral reactivation plays a role?

A: The re-contact process of iciHHV-6+ subjects is currently ongoing. Once these have agreed to donate blood, several additional studies will be conducted. RNA from iciHHV-6+ and iciHHV-6- subjects will be analyzed for the presence of HHV-6 transcripts

Q: You list several conditions associated with shortened telomeres. They are all conditions that have also been associated with HHV-6 reactivation: cardiovascular disease, hematopoietic dysfunction, pulmonary fibrosis, liver disease, degenerative diseases and cancer. Is it possible the shortening in these conditions could be influenced by community acquired HHV-6 that integrates and then reactivates?

A: This is unlikely as the number of cells infected and carrying integrated HHV-6 from community acquired HHV-6 is likely to be very low. Thus, even though HHV-6 integration/reactivation affects telomere length, the fact this will occur in a limited number of cells is likely to be without major consequences.

Q: The difference in the prevalence of angina in ciHHV-6+ women (14.3%) and ciHHV-6- (2.2%) women was striking, with a 6.5x higher level in affected women. Men showed a much smaller variance. Do you believe women may be more affected by their ciHHV-6 status?

A: It certainly looks that way. However, the statistical analyses conducted suggest that the difference in angina prevalence observed between women and men are not statistically significant.   Additional studies may help resolve this issue.

Q: None of the ciHHV-6+ individuals had MS in spite of a prevalence of .7 % in female controls. Some have speculated that ciHHV-6 might be protective for MS due to tolerance and decreased antibody response secondary to tolerance. Do you believe this might be a possibility?

A: I think the numbers of subjects is too low to draw any conclusion.

Q: 37% of ciHHV-6+ females were taking allergy medications, compared to female controls at 20%. HHV-6 is activated in extreme drug hypersensitivity reactions. Does this suggest an avenue worth exploring?

A: I do think so. This is something worth investigating.

Q: You determined individuals to be ciHHV-6 when the copy number was >0.5 per cell in DNA extracted from whole blood.  Were there significant numbers of individuals who had between 0 and .5 copies per cell? Did a significant number have >1 copy per cell?

A: There were a few subjects with very low HHV-6 copy number. Since this was not the focus of our study, we did not investigate this further. As far as subjects with >1 HHV-6 copy/cell, we found 5 with >1.5<2.5. If we can have access to blood from these subjects, these will be studied in greater detail.

For more information, read the full article HERE.

L-R: Louis Flamand, Isabelle Dubuc, Annie Gravel