Explanation of \’excessive and premature\’ CVD mortality in bipolar disorder?

An early predictor of cardiovascular disease (CVD) has been found in young people with bipolar disorder (BD), in new findings that may explain heart disease-related \’excessive and premature mortality\’ in this patient population.

The researchers found that higher scores on the reactive hyperemia index (RHI), a measure of endothelial function, were related to mood severity in patients with higher scores for mania, but not for depression. These results persisted even after accounting for medications, obesity, and other cardiovascular risk factors (CVRF).

\”From a clinical perspective, these findings highlight the potential value of vascular health integration in the assessment and management of youth with BD, and from a scientific perspective, these findings warrant further research focused on the shared biological mechanisms linking the vascular health and mood symptoms of BD,” said senior investigator Benjamin Goldstein MD, PhD, full professor of psychiatry, pharmacology and clinical sciences of psychology, University of Toronto, Canada Medscape Medical News.

The study was published online May 1 in Journal of Clinical Psychiatry.

\”Excessively present\”

BD is associated with \”excessive and premature cardiovascular mortality,\” and CVD is \”excessively present\” in BD, exceeding what can be explained by traditional cardiovascular risk factors, psychiatric medications, and substance use, the researchers note.

“In adults, more severe mood symptoms increase the risk of future CVD. Our focus on endothelial function has increased due to the fact that CVD is rare in young people, while endothelial dysfunction considered a precursor to CVD can be evaluated in youth,” said Goldstein, who holds the RBC Investments chair in child mental health and developmental psychopathology at the Center for Addiction and Mental Health, where he is director of the Center for Youth Bipolar Disorder.

For this reason, he and his colleagues were \”interested in investigating whether endothelial dysfunction was associated with mood symptoms in youth with BD.\” Ultimately, the motivation was to \”inspire new therapeutic opportunities that could simultaneously improve both cardiovascular and mental health.\”

To investigate this question, the researchers studied 209 youth, aged 13 to 20 years (n = 114 with BD and 94 healthy controls [HCs]).

In the BD group, there were 34 BD-euthymia, 36 BD-depressed, and 44 BD-hypomanic/mixed; and within the depression or hypomania/mixed features groups, 72 had clinically significant depression.

Participants had to be free from chronic inflammatory disease, use of medications that could address traditional CVRF, recent infectious disease, or neurological conditions.

Participants\’ bipolar symptoms, psychosocial functioning, and family history were assessed. Additionally, they were questioned about treatment, physical and/or sexual abuse, smoking status, and socioeconomic status. Height, weight, waist circumference, blood pressure, and blood tests to evaluate CVRFs, including C-reactive protein (CRP), were also assessed. RHI was measured by pulse amplitude tonometry, with lower values ​​indicating poorer endothelial function.

Positive effect beneficial?

Compared with HCs, there were fewer white participants in the BD group (78% vs 55%; P<.001). The BD group also had higher Tanner stage development scores (stage 5: 65% vs 35%; P=.03; v=0.21), highest body mass index (BMI; 24.44.6 vs 22.04.2; P<.001; d=0.53) and higher CRP (1,943.99 vs 0.760.86; P=.009; d=0.40).

After controlling for age, gender, and body mass index (f 3.202=4.47; P=.005; P 2 =.06), the researchers found significant between-group differences in RHI.

Post hoc pairwise comparisons showed that RHI was significantly lower in the BD-depressed group than in the HC group (P=.04; d=.4). Furthermore, the BD-hypomanic/mixed group had a significantly higher RHI than the other BD groups and the HC group.

BD-euthymic P = .02; d=.55
BD-depressed P < .001; d=.79
HC P = .04; d=0.55

RHI was associated with higher mania scores (=.26; P=.006), but there was no similar significant association with depression mood scores (=.01; P=.90).

Mood state differences in RHI and the RHI-mania association remained significant in sensitivity analyzes examining the effect of current medication and CVRF use, including lipids, CRP, and blood pressure on RHI.

\”We found that youth with BD who experienced a depressive episode had lower endothelial function, while youth with BD who experienced a hypomanic/mixed episode had higher endothelial function, compared with healthy youth,\” Goldstein said.

There are several mechanisms potentially underlying the association between endothelial function and hypomania, the researchers note. For example, they report that positive affect is associated with increased endothelial function in normative samples, so hypomanic symptoms, including euphoria, may have similar beneficial associations, although those benefits probably do not extend to mania, which has been associated to cardiovascular risk.

They also point to several limitations in the study. The cross-section design \”prevents making inferences about the temporal relationship between RHI and mood.\” Additionally, the study only focused on hypomania, so \”we can\’t draw any conclusions about mania.\” Additionally, the HC group had a \”significantly higher proportion\” of white participants and lower Tanner stage, so \”may not be a representative control sample.\”

However, the researchers conclude that the study \”adds to existing evidence for the potential value of integrating cardiovascular therapeutic approaches in BD,\” noting that more research is needed to elucidate the mechanisms of the association.

Observable changes in youth

Commenting for Medscape Medical NewsJess G Fiedorowicz, MD, PhD, chief and chief, department of mental health, Ottawa Hospital Research Institute, Canada, noted that people with BD \”have a much higher risk of CVD, which tends to develop earlier and shortens the life expectancy of more than a decade\”.

This cardiovascular risk \”appears to be acquired over the long-term course of the disease and proportionate to the persistence and severity of mood symptoms, implying that mood syndromes, such as depression and mania, may themselves induce changes in body relevant to CVD,” said Fiedorowicz, who is also a professor in the department of psychiatry, School of Epidemiology and Public Health, and Senior Research Chair in Adult Psychiatry, Brain and Mind Research Institute, University of Ottawa, Canada, and is not been involved in the study.

The study \”adds to a growing body of evidence that mood syndromes can enact physiological changes that may be relevant to CVD risk. An important aspect of this study is that this can also be observed in a sample of young people,\” he said.

J Clin psychiatry. Published online May 1, 2023. Full text

This study was funded by the Canadian Institutes of Health Research and a University of Toronto Miner\’s Lamp Innovation Fund. Goldstein and coauthors disclose no relevant financial relationships. Fiedorowicz receives honorarium from Elsevier for his work as editor-in-chief of the Journal of Psychosomatic Research.

Batya Swift Yasgur MA, LSW, is a freelance writer with a consulting firm in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of numerous consumer-oriented health books, as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memory of two brave Afghan sisters who told her their story).

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