|Year : 2018 | Volume
| Issue : 3 | Page : 78-84
Impact of mood on endothelial function and arterial stiffness in bipolar disorder
Samantha L Schmitz1, Oluchi J Abosi2, Jane E Persons3, Christine A Sinkey4, Jess G Fiedorowicz5
1 Department of Psychiatry, The University of Iowa, Iowa City, Iowa, USA
2 Department of Psychiatry; Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, USA
3 Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
4 Department of Ophthalmology, The University of Iowa, Iowa City, Iowa, USA
5 Department of Psychiatry; Department of Epidemiology, College of Public Health; Roy J. and Lucille A. Carver College of Medicine; François M. Abboud Cardiovascular Research Center; Department of Internal Medicine; Iowa Neuroscience Institute, Obesity Research and Education Initiative, The University of Iowa, Iowa City, Iowa, USA
|Date of Submission||05-Aug-2019|
|Date of Decision||27-Aug-2019|
|Date of Acceptance||28-Aug-2019|
|Date of Web Publication||27-Sep-2019|
Jess G Fiedorowicz
200 Hawkins Drive W278GH, Iowa City, Iowa 52242-1057
Source of Support: None, Conflict of Interest: None
Background: Previous research on bipolar disorder demonstrates greater-than-expected vascular dysfunction later in the course of illness, proportionate to the cumulative burden of mood symptoms. However, little is known about the effect of acute mood states on vascular function. Here, we examine the relation between vascular function and mood state in individuals with bipolar disorder. Materials and Methods: This prospective study followed forty individuals with bipolar disorder for up to 6 months. The participants were assessed for mood state and vascular function at baseline, 2 weeks, and 6 months. Mood state was determined using the clinician-administered Montgomery–Šsberg Depression Rating Scale and Young Mania Rating Scale. Vascular function was assessed by flow-mediated dilation (FMD) of the brachial artery, forearm vascular resistance (FVR), and arterial stiffness. Results: The participants had a mean age of 30.1 years, and 75% were male. Primary outcome measures such as FMD and nitroglycerine-mediated dilation were not found to have statistically significant associations with depressive or manic symptoms. In unadjusted models, higher manic symptoms were significantly associated with increased FVR nitroprusside-mediated dilation and diastolic blood pressure. In adjusted models, higher depressive symptoms were significantly associated with increases in augmentation index adjusted for heart rate of 75 bpm, and higher manic symptoms remained associated with increases in diastolic blood pressure. Conclusion: FMD may have limited sensitivity as a biomarker for measuring short-term effects of mood state. Long-term prospective studies are needed to clarify the temporal relation between chronic mood symptoms and vascular function in bipolar disorder.
Keywords: Arterial stiffness, bipolar disorder, cardiovascular risk, endothelial dysfunction
|How to cite this article:|
Schmitz SL, Abosi OJ, Persons JE, Sinkey CA, Fiedorowicz JG. Impact of mood on endothelial function and arterial stiffness in bipolar disorder. Heart Mind 2018;2:78-84
|How to cite this URL:|
Schmitz SL, Abosi OJ, Persons JE, Sinkey CA, Fiedorowicz JG. Impact of mood on endothelial function and arterial stiffness in bipolar disorder. Heart Mind [serial online] 2018 [cited 2022 Nov 27];2:78-84. Available from: http://www.heartmindjournal.org/text.asp?2018/2/3/78/268091
| Introduction|| |
The risk of cardiovascular death for bipolar disorder is approximately two times greater than expected from the general population. This elevated risk persists even after accounting for the high prevalence of cardiovascular risk factors present in individuals with bipolar disorder.,, Long-term depressive and manic symptom burden has been independently linked to poor endothelial function, which plays a role in the development of atherosclerosis and subsequent cardiovascular morbidity and mortality.,, The precise mechanism that leads to the development of endothelial dysfunction in bipolar disorders is unknown; however, the persistence and duration of mood syndromes have been associated with impaired vascular function.,
Biomarkers of endothelial function
The majority of studies addressing the impact of mood on biomarkers of endothelial function are cross-sectional.,,, Available prospective studies have primarily examined increased mortality in patients with bipolar and other mood disorders due to suicide rates, other cardiovascular risk factors, or the effects of antipsychotic medications prescribed.,, Fiedorowicz et al. demonstrated in a cohort of individuals from the National Institute of Mental Health Collaborative Depression Study that participants with a greater longitudinal burden of manic symptomatology over follow-up exhibited subsequent poorer endothelial function as measured by flow-mediated dilation (FMD) of the brachial artery. However, there are no prospective studies that establish a temporal relationship between specific mood states in bipolar disorder and changes in endothelial function. Endothelial dysfunction is an important outcome of interest because it plays a role in the development of atherosclerosis, which in turn leads to increased cardiovascular morbidity and mortality. Well-validated measures of endothelial function include FMD, forearm vascular resistance (FVR), and aortic stiffness, which are useful indicators for future cardiovascular events and mortality.,,,,,
Purpose of the research
The purpose of this study was to clarify the temporal relations between acute mood episodes and vascular function; to accomplish this, we utilized FMD, nitroglycerine-mediated dilation, FVR, and aortic stiffness measures in a prospective study to determine if burden of depressive and manic mood symptoms is associated with increased endothelial or other vascular dysfunction over short term (2 weeks) or intermediate term (6 months). We hypothesized that the severity of mood symptoms would be associated with worsened endothelial function, as measured by FMD, within 6 months.
| Materials and Methods|| |
A total of forty participants were identified from a prospective cohort, originally described by Fiedorowicz et al., looking at the role of incident antipsychotic use and blood vessel function in a sample of individuals broadly defined as bipolar or related mood disorders (Diagnostic and Statistical Manual of Mental Disorders-IV defined bipolar I; bipolar II; bipolar not otherwise specified; schizoaffective disorder; and major depressive disorder with psychotic features). All participants completed an evaluation to sign consent prior to providing written informed consent in this institutional review board-approved study. Participants were recruited between 2007 and 2014 from the institution using electronic medical records, electronic mail, targeted mailings, clinical referral, and advertisements. This sample was recruited from individuals with acute illness most likely to begin antipsychotic medications estimated by a locally derived propensity score based on age, presence of mania and/or psychosis, marital status, and lithium use. Exclusion criteria included neoplasm, untreated thyroid disease, pregnancy or planned pregnancy, alcohol abuse in the past month (≥5 drinks on a single occasion in the past month and ≥2 on CAGE), any use of illicit drugs in the past month, and alcohol or substance dependence in the past year.
Vascular outcome measures
Prior to vascular measure assessments, all participants confirmed with a trained research nurse that they had fasted for at least 12 h and abstained from smoking tobacco in the preceding 2 h before measurements were taken. Vitals were measured after the participant rested in a seated position for 5 min. Height and weight were measured without shoes in light clothing.
FMD was assessed noninvasively via ultrasound measurement of brachial artery diameter during changes in brachial artery flow. Images of brachial artery diameter and Doppler velocities from the center of the vessel were recorded using a 10–13 MHz linear array transducer ultrasound system (Biosound ESAOTE, Indianapolis, IN). After obtaining baseline diameter and velocity measures, an occluding forearm cuff was placed on the forearm just below the antecubital fossa and inflated 50 mmHg above systolic blood pressure for 5 min. The brachial artery diameter and Doppler velocities were continuously recorded before, during, and after cuff deflation. The resulting change in arterial diameter from baseline to 1 min measured nitroglycerine-mediated dilation, a measure of endothelium-dependent dilation. Following a return to baseline (10 min of rest), 400 μg of sublingual nitroglycerine was administered. Brachial artery diameter and velocity were measured for an additional 6 min. The resulting change in arterial diameter from baseline to 4 min after nitroglycerine administration measured endothelium-independent FMD.
Arterial stiffness was captured using pulse wave velocity – the velocity of the blood pressure pulse waveform is dependent on the stiffness of the artery along which the pulse is traveling; increases in these values reflect an increase in arterial stiffness., Carotid, radial, and femoral pressure waveforms as well as electrocardiogram waveforms were recorded using SphygmorCor technology (AtCor Medical, Sydney, Australia). Aortic systolic pressure, augmentation pressure, and augmentation index adjusted for a heart rate of 75 measurements were derived from radial pressure waveforms and brachial blood pressure measurements using pulse wave analysis software. Pulse wave velocity was calculated from the mean R-wave time difference and the arterial path length between the superficial carotid and femoral artery sites.
FVR was assessed through administration of the following three vasoactive agents: acetylcholine, an endothelium-dependent vasodilator; nitroprusside, an endothelium-independent vasodilator; and verapamil, an endothelium- and nitric oxide-independent vasodilator as previously described., Forearm blood flow was measured by venous occlusion plethysmography using indium/gallium-in-silastic strain gauges. The three vascular agents were administered through brachial artery infusion at three doses as follows: acetylcholine (3, 10, and 30 μg/min), nitroprusside (1, 3, and 10 μg/min), and verapamil (10, 30, and 100 μg/min). Verapamil was administered last in all patients due to its long half-life. Each drug was administered over the course of 18 min, increasing the dose every 6 min. The percentage change of flow ratio in response to the drug was utilized as the outcome measure.
Exploratory outcomes were assessed from a venous blood sample and included predetermined cardiovascular risk factors namely low-density cholesterol, triglycerides, high-density cholesterol, C-reactive protein, and insulin resistance (determined using the Homeostatic Model Assessment for Insulin Resistance calculated from fasting blood glucose and insulin).
Individuals' diagnostic information, clinical characteristics, and medical history were obtained through direct interviewing with a board-certified psychiatrist (JGF). Mood symptoms were characterized for each visit using the Montgomery–Šsberg Depression Rating Scale (MADRS) for depressive symptoms and the Young Mania Rating Scale (YMRS) for manic symptoms., Current psychiatric treatment was not directed by the study and was collected during each study visit. Medication exposures were recorded and pooled into the following broad classes for analyses:first-generation antipsychotics, second-generation antipsychotics, selective serotonin reuptake inhibitors, lithium, lamotrigine, valproic acid derivatives, carbamazepine, benzodiazepines, and other antidepressants.
Descriptive statistics were reported for all participants who completed at least one visit with mood ratings and vascular measurements. Primary analyses were conducted using linear mixed models with a random intercept term to account for repeated observations within participants. The vascular outcomes were modeled as dependent variables and mood symptoms were modeled as independent variables. Models were adjusted for age (continuous, linear effect), sex, and medication group exposures. Time effects were modeled as a categorical variable, a preferred choice for this analysis with unevenly spaced times designed to distinguish acute from subacute effects. All analyses were conducted using R 3.5.2 (R Core Team, Vienna, Austria) and package “nlme.”,
| Results|| |
Baseline clinical and sociodemographic characteristics of the sample are illustrated in [Table 1] and [Table 2]. This sample had a mean age of 30.1 years (standard deviation = 9.4, range: 18–55 years), and 75% were male. During the study, 45% of the participants were being treated with one or more mood stabilizer medications, 63% with antipsychotics, and 50% with antidepressants; of these, 20% received combination therapy of both mood stabilizers and antipsychotics. Both depressive and manic symptoms, measured by mean MADRS and YMRS scores, reduced from baseline to 6 months. Mood rating scales, vascular measurements, and cardiovascular risk factors and vitals from each visit (baseline, 2 weeks, and 6 months) are highlighted in [Table 3].
Primary outcome measures such as FMD and nitroglycerine-mediated dilation were not found to have statistically significant associations with depressive or manic symptoms over time. Of the secondary and exploratory outcome measures, only augmentation index adjusted for heart rate of 75 (AIX@75) was statistically significantly associated with depressive symptoms over time (β = 0.216, standard error [SE] = 0.101, P = 0.04) when adjusted for age, sex, and medications. In unadjusted models, increases in mania symptoms were statistically significantly associated with increases in both FVR nitroprusside-mediated dilation (β = 8.840, SE = 4.068, P = 0.04) and diastolic blood pressure (β = 0.216, SE = 0.096, P = 0.03). After adjustment, diastolic blood pressure (β = 0.271, SE = 0.099, P = 0.01) remained statistically significantly associated with mania symptomology. No other secondary or exploratory vascular outcome measures were associated with manic or depressive symptoms. Results for linear mixed models for depression and manic symptomology on endothelial function are summarized in [Table 4] and [Table 5], respectively.
|Table 4: Effects of depressive symptoms on vascular outcomes: Linear mixed model analysis|
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|Tables 5: Effects of mania symptoms on vascular outcomes: Linear mixed model analysis|
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| Discussion|| |
In this prospective study of the influence of mood state on vascular function in bipolar disorder, we did not observe any acute or subacute changes in our primary outcome of FMD corresponding to mood state. There were several positive secondary outcomes, including AIX@75, nitroprusside-mediated (endothelium independent) forearm resistance vessel dilation, and diastolic/mean arterial blood pressure. With regard to depressive symptoms, we observed increases in arterial stiffness (AIX@75) with greater MADRS scores. For manic symptomology, we observed better endothelium-independent resistance vessel function, measured by FVR in response to intra-arterial nitroprusside, and higher diastolic blood pressure with a higher YMRS score. As secondary outcomes, these findings should be treated as hypothesis generating. Overall, while predominantly negative, the results are informative for future study of the impact on mood on vascular risk.
In the present study, depression was associated with AIX@75 in an adjusted model, and mania was marginally associated. These findings are consistent with that of previous studies. Oulis et al. observed greater arterial stiffness in patients with depression compared to controls; however, after 6 weeks of treatment, patients experienced acute reversals of arterial stiffness in association with depression severity. Similarly, Kokras et al. found acute improvements in arterial stiffness associated with decreased depression in patients that reached remission after receiving 6 months of treatment. Taken together, these studies suggest that mechanisms that can acutely change arterial stiffness, beyond atherosclerosis which does so more insidiously, may be involved. Such reported mechanisms include inflammation,,, unhealthy lifestyle habits, medications, autonomic nervous system stress,, and blood pressure.,
Our findings linking changes in manic symptoms with diastolic blood pressure and mean arterial pressure provide some insight. Cardiovascular mortality is elevated in those with greater mania symptomology., This has generally been assumed to develop over the long-term course of illness in relation to cardiometabolic consequences (e.g., weight gain, dyslipidemia) of illness and treatments thereof and through the development of atherosclerosis. The acuteness of the changes in blood pressure observed, however, suggests relevance for other mechanisms, perhaps involving the autonomic nervous system, which has been surprisingly understudied with mania.
An unexpected finding in our study was mania acutely associated with an apparent protective effect on FVR with nitroprusside in the unadjusted model. This finding suggests that acute physiological changes associated with mania may also improve endothelium-independent vasodilation. Nitroprusside acts as a nitric oxide donor, and increased dilation might suggest greater responsiveness to the vascular smooth muscle to this stimulus. Both the neuronal and endothelial isoforms of nitric oxide synthase have been associated with bipolar disorder, although these genetic associations are modest and this small sample was not genotyped. While we attempted to adjust for medication use, our study was not well designed to do so, and the participants had several changes in medications in response to acute episodes. In an in vitro model, lithium was shown to slightly increase endothelium-dependent vasodilation and had no impact on endothelium-independent vasodilation. Valproic acid has been shown to increase nitric oxide production in vitro. Interestingly, in our model that adjusted for medication use with indicator variables for broad categories, FMD was found to be marginally associated with manic symptoms in the adjusted model. This and our aforementioned finding with nitroprusside-mediated dilation of forearm resistance vessels contrast the previously observed long-term burden of manic symptoms on FMD., It is possible that biomarkers of cardiovascular risk may differ within acute mood episodes from those of acquired risk over the long-term course of illness. While this might seem paradoxical, acute and chronic stress are differentiated by several wide-ranging physiological distinctions.
This is the first prospective study that looks specifically at the vascular function in different mood states in participants with bipolar disorder. A notable strength of the study is its prospective nature, which allows for assessment of the temporal relationships between the vascular function and mood symptoms. The study also utilized well-validated, clinician-administered mood scales to measure the severity of mood symptoms. There are several important limitations to the study. The study had a small sample size and missing data which increased the potential for Type II error. Inclusion of participants with a diagnosis of bipolar disorder was based on clinical diagnosis with a broad definition of bipolar disorder. The ability to detect associations may be limited if mood symptoms influence vascular function only in diagnostic subgroup. Our co-primary outcomes were negative, and the positive results observed were from secondary analyses. The potential for a spurious finding or Type I error must subsequently be considered. The follow-up time may not have been long enough to capture vascular changes related to mood episodes if the effects of mood symptoms on vascular measures are delayed or accumulated over the long-term course of illness. Additional prospective studies of individuals experiencing new episodes may be able to better discern any acute effects of mood, perhaps focusing on other physiological measures.
| Conclusion|| |
More sensitive biomarkers are needed to assess the relevant mood-induced physiological changes that influence the risk of vascular disease in small samples to elucidate how the physiological changes associated with mood may impact the dramatic elevated risk of vascular disease seen in mood disorders. There is a need for an extended prospective study of larger samples to discern the temporal relationships between mood states and changes in intermediate phenotypes for vascular disease, such as endothelial function.
The authors thank Janie Myers, Lois Warren, and Ashley Schumacher for their assistance in recruiting participants.
Financial support and sponsorship
This study was financially supported by the National Institutes of Health (K23MH083695, P01HL014388, and K23MH085005).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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