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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 1  |  Issue : 3  |  Page : 112-118

Greater N-Acetylaspartate to creatine ratio within left anterior insula predicts sympathetic imbalance in postmenopausal women living with hypertension and/or HIV


1 Department of Psychology, University of Miami, FL, USA
2 Department of Radiology; Department of Biomedical Engineering, Miller School of Medicine, FL, USA
3 Department of Medicine, Miller School of Medicine, FL, USA

Date of Web Publication17-Jul-2018

Correspondence Address:
Dr. Roger C McIntosh
1120 NW 14th Street RM 1527, Miami, Florida 33136
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/hm.hm_18_17

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  Abstract 

Context: Brain metabolite ratios derived from magnetic resonance spectroscopy (MRS) has been used to document changes in neuronal viability, glial activation and inflammation associated with Human Immunodeficiency Virus (HIV) infection and cardiovascular disease. Aims: To determine whether brain metabolite ratios in the left anterioar insula predicts cardio-autonomic regulation indexed by the ratio of low- to high-frequency heart rate varaibility (LF:HF) after accounting for post-menopausal age, HIV and hypertensive (HTN) status. Design: Thirty women, (n=14 HIV+ and n=16 HTN+) with an average age of 54.5 (SD=6.4) years and no history of neurological disease were recruited for the study. Methods: After conventional MR imaging, single-voxel 1H-MRS (TR = 1500 msec; TE = 35 msec) was performed by using a PROBE-SV system implemented on a 3T GE Discovery MR750 scanner. Shift-selective imaging pulses for water suppression were acquired from a voxel placed in the midline of the left anterior insula with an average voxel size of 15×15×15 mm. Heart rate variability was estimated over a 7 minutes resting state scan using an MR-compatible photoplethysmogram. Statistics: A stepwise regression analysis controlling for (1) age, disease status (HIV+ and HTN+) was modelled separately for the ratio of N-acetylaspartate (NAA), Myo-inostol (mI), and Choline (Ch) to Creatine (Cr) ratios to predict LF:HF. Results: Higher ratios of NAA/Cr were associated with lower LF:HF (β= -.393, t(29)= -2.26, p= .033). Ratios of mI:Cr and Cho:Cr did not predict LF:HF. Conclusions: Decreased neuronal viability in the left anterior insula, indexed by lower NAA/Cr metabolite ratios explain a significant proportion of the variance in the skew towards sympathetic overarusal in postmenopausal women at risk for cerebrovacular disease.

Keywords: Blood pressure, chronic disease, human immunodeficiency virus, menopause, parasympathetic, sympathetic


How to cite this article:
McIntosh RC, Lobo JD, Fajolu O, Reyes E, Pattany PM, Kolber MA. Greater N-Acetylaspartate to creatine ratio within left anterior insula predicts sympathetic imbalance in postmenopausal women living with hypertension and/or HIV. Heart Mind 2017;1:112-8

How to cite this URL:
McIntosh RC, Lobo JD, Fajolu O, Reyes E, Pattany PM, Kolber MA. Greater N-Acetylaspartate to creatine ratio within left anterior insula predicts sympathetic imbalance in postmenopausal women living with hypertension and/or HIV. Heart Mind [serial online] 2017 [cited 2022 Aug 10];1:112-8. Available from: http://www.heartmindjournal.org/text.asp?2017/1/3/112/236928


  Introduction Top


The symptoms of cardiovascular disease (CVD) consist of chronic cerebral circulatory disorders, ischemia, hypoxic changes, and volumetric thinning. The application of magnetic resonance spectroscopy (MRS) is a noninvasive diagnostic test to measure the biochemical changes in the brains of the patients with neurodegenerative disease.[1] The metabolic moieties of N-acetylaspartate (NAA), myoinositol (ml), choline (Ch), and creatine (Cr) are often used to assess the statuses of neuronal glial activation and inflammation. Of all, the NAA level is widely accepted as a prognostic marker of neuronal density and viability, in those patients with inflammation, an increased ml level predicts glial proliferation and the changes in cell sizes and the Ch level is an established marker for evaluating membrane density and integrity.[2] Although much of this work has focused on age-related neurodegenerative diseases, there has been increased interest in status of brain neuroglia in individuals with CVD. In patients with postoperative carotid endarterectomy a significant decrease in ratio of NAA/Cr and Cho/Cr was reported along with a decrease in cognitive function.[3] In the elderly patients with increased carotid artery intima-media thickness, a lower ratio of NAA/Cr was also present.[4] In a study that compared healthy controls to diabetic patients with hypertension (HTN) lower NAA ratio and an increased Cho ratio within the bilateral prefrontal cortex were observed in the patient group.[5] The results revealed that peripheral small artery disease was related to the decreases in neuronal integrity and the increases in membrane disintegration, respectively. Some interpret the localization of CVD-related alterations in metabolite concentration as a causative factor leading to the manifestation of cardiovascular complications. Cardio-autonomic neuroscience has implicated structural alterations to the medial prefrontal, anterior cingulate, and most notably insular cortex in the regulation of heart rate and blood pressure (BP).[6],[7],[8] For example, compared to normotensive controls patients with controlled and resistant HTN show decreases in frontal NAA/Cr along with increases in ml/Cr ratio.[9] Most recently, hypertensive patients were found to have lower NAA and Cho ratios within the bilateral anterior insula and thalamus when compared to normotensive individuals.[10] Altogether, a bidirectional link between small vessel peripheral disease or cardiovacular regulation and metabolite indices of change in neural viability of frontal brain regions implicated in cardio-autonomic regulation.

CVD comorbidity is prevalent in persons living with human immunodeficiency virus (HIV).[11] Also evident are increased rates of HIV-related neurodegeneration with advancing age [12],[13] There is ample literature supporting the clinical relevance of brain metabolite ratios in HIV disease. HIV + individuals both on and off combination antiretroviral therapy (ART) show lower NAA and Cho ratios throughout the cingulate gyrus, deep frontal white matter, and subcortical parietal white matter.[14],[15] There is also MRS evidence to suggest both CVD-comorbidity and advancing age interact to exacerbate HIV-related neurodegeneration. A study of patients on ART compared to healthy controls found an interaction between age and HIV on reduced frontal NAA.[12] Moreover, elevated Framingham risk scores were associated with the lower posterior cingulate cortex and caudate NAA in this study. HIV patients also have elevated risk for HTN which may be contributed to by autonomic derangement and show a skew toward sympathetic over-arousal that has been observed in this population.[16],[17],[18] The aim of the current study was to determine whether metabolite ratios of the left anterior insula predict sympathetic/parasympathetic ratio in HIV + and HIV-negative postmenopausal women with elevated risk for HTN. Based on prior research implicating the anterior insula in cardioautonomic regulation,[19],[20] reports of lower metabolite concentrations within this region in HIV + patients,[10] and the compounding effects of age and menopause on cardioautonomic regulation,[21],[22],[23],[24] ratios indicative of greater insula neurodegeneration are hypothesized to be associated with a skew toward greater sympathetic tone.


  Subjects and Methods Top


A total of 44 patients (21 HIV+) were enrolled in the study. Inclusion criteria for the HIV+ group included postmenopausal status, (≥12 months since the past menstrual cycle) and on stable ART (≥6 months) with HIV+ serostatus confirmed by blood test. Criteria for exclusion included: (1) current or lifetime history of a diagnosed CVD condition, (e.g., HTN, congestive heart disease, etc.), or heart surgery; (2) current or lifetime diagnoses of cancer, kidney/liver disease, type 1 or type 2 diabetes; (3) cerebrovascular accident or infarction; (4) current substance abuse or treatment; (5) current treatment for mental illness; (6) history of cerebrovascular accident, loss of consciousness; (7) current treatment or diagnosis of psychiatric illness including Axis 1 or 2 disorders; (8) metal implants or debris within the body; (9) current pregnancy or breast feeding; or (10) current hormone replacement therapy.

Of the enrolled patients whom completed the MRS scan, a total of 14 women were excluded due to excessively noisy or incomplete psychophysiological data recorded during the resting state period. This resulted in a total of 14 HIV+ and 16 HIV− women that were included in the final data analysis. BP was measured during physical intake to confirm hypertensive status after the participant had rested for at least 5 min in a seated position, using an appropriately sized cuff placed on the left arm using a continuous digital BP monitor (CNAP ® Monitor 500 HD; Graz, Austria). Anthropometrics including weight and height were also collected. Psychological data were collected in face-to-face interviews using standardized questionnaires administered by a graduate psychology trainee. Prior to the MRS scanning session subjects were oriented to a mock MRI scanner where they were introduced to the various scanner noises and timing of study protocols. The 7 min resting state scan and 5 min MRS probe were preceded an interspersed by 4–6 min T1-weighted structural scans. The study design was approved by the independent ethnic committee at the study site. All participants signed informed consent before participating in the study.

1H-magnetic resonance spectroscopy data acquisition

1H-MRS data were acquired using a 3-T GE Discovery MR750 MRI scanner (GE Medical Systems, Milwaukee, WI, USA), using a 32-channel-phased array head coil to provide the highest signal to noise. The scan protocol consisted of a T1-weighted Magnetization Prepared Rapid Gradient-Echo (MPRAGE) sequence with following parameters: Sagittal slices, repetition time (TR) = 9.18 ms, time to echo (TE) = 3.68 ms, flip angle = 12°, field of view 256 mm, in-plane matrix 256 × 256, which results in 1.0-mm isotropic voxels. These images were used to aid in placement of the MRS voxel. Single voxel 1H-MRS Point Resolved Spectroscopy acquisition was used, the Extended dynamic range option was selected for the acquisition. Chemical shift-selective pulse was used for water suppression, and the voxel was placed in the midline of the left anterior insula, with the following parameters: TE = 35 ms, TR = 1500 ms, with 128 averages voxel size of 15 mm × 15 mm × 15 mm. Anatomical localization of voxel placement was based on the Montreal Neurological Institute-152  Atlas More Details and positioning was guided by the T1 MPRAGE image as shown in [Figure 1]. All spectra were shimmed (using automatic and manual higher-order shimming). All spectra were visually inspected and poorly fitted metabolite peaks as reflected by excessive noise. The RMS noise of the experimental data was measured after baseline correction in the spectral range between −1.8 and −3.6 ppm.[25] In addition, signal to noise ratios for Cr were excluded from further analysis if the signal to noise ratio was <40.0.
Figure 1: Magnetic resonance spectroscopy seed region for the left anterior insula probe and corresponding metabolite ratios

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Photoplethysmography

Participants were outfitted with an MRI-compatible photoplethysmogram (PPG) to identify inter-beat intervals and estimate heart rate variability (HRV) per standards recommended by the Task Force of the European Society of Cardiology.[26] The assessment of HRV from finger-tip photoplethysmography is shown to have very high correspondence with that derived from electrocardiography.[27] Resting heart rate was recorded from the index finger of the left hand and averaged over the entire period of the 7 min resting state scan. The PPG signal was conveyed through an A/D converter (Biopac MP150, Biopac system Inc., Santa Barbara, CA) continuously sampled at 500 Hz. Before visual inspection and flagging of a peak detection algorithm was used to determine the interbeat intervals for assessment of both average HR and as raw data for the analysis of HRV.

Sympathetic/parasympathetic balance

Heart rate variation during normal breathing was recorded, with subject supine, awake, and resting for 7 min. The time series was subjected to frequency domain analysis of HRV using a nonparametric method of fast Fourier transformation after being edited manually for artifacts and ectopic beats. The Biopac software provides a peak detection algorithm to find the “R” wave at a resampling rate of 6 Hz. A minimum of 256 data points were required to perform a spectral analysis over the course of 7 min of recording. The power frequency spectrum was then quantified into standard frequency-domain measurements including high-frequency (HF 0.15–0.4 Hz), low-frequency (LF 0.04–0.15 Hz). The ratio of LF/HF was then quantified as a final estimate of sympathetic/parasympathetic balance.

Statistical analyses

All the statistical analyses were performed with 30 participants. First, Pearson coefficients were estimated among all study variables to produce a correlation matrix [Table 1] that was evaluated by a statistical significance of P < 0.05. Three hierarchical regression models were specified with the primary aim of assessing the amount of variance in sympathetic/parasympathetic balance accounted for by NAA, Cho, and mI ratios after controlling for postmenopausal age in the first stage of the model and disease status (HIV + and HTN+) in the second stage of the model. Each of the three models were distinguished by the brain metabolite ratio entered into the third step of the model, i.e.,, (NAA/Cr, Cho/Cr, and mI/Cr). A significance test for the change in variance (ΔR 2) at each step of the model was evaluated in addition to beta coefficients and overall significance for each model was evaluated at the P < 0.05 level. All analysis were performed using PASW, Statistics 24 (Release 24.0.0; SPSS Inc., Chicago, IL, USA).
Table 1: Bivariate correlations between study variables separated by human immunodeficiency virus + (bottom left) human immunodeficiency virus - (top right)

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  Results Top


Demographics

Demographic and CVD information is provided in [Table 2]. The average age post-menopause of the sample was 8.1 years. Of the 14 HIV + subjects, 6 (42.9%) had a past diagnosis of AIDS, and 14 (100%) were currently taking ART. Of the 12 (40%) women in the sample reporting HTN diagnosis, 6 (50%) were currently taking anti-hypertensive medication.
Table 2: Sociodemographic and disease information

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Cross-correlations

[Table 1] presents correlation coefficients for the study variables separated as a function of HIV + and HIV-negative status. When the associations of the LF: HF ratio with the various SPEC metabolites were evaluated, only the NAA/Cr values significantly decreased with increasing LF: HF ratios (r = −0.469, P = 0.009). There were no associations found between mI and Cho ratios and LF:HF ratio. The correlation between HTN status and LF: HF ratio also trended toward significance in the full sample (r = 0.326, P = 0.078). There were no other significant correlations present.

Hierarchical regression

[Table 3] displays results from the stepwise regression model for NAA/Cr was significant F (4, 29) = 3.04, P = 0.036. The model revealed that the increase in the LF: HF ratio significantly predicted lower NAA/Cr in the left anterior insula t (29) = −2.26, P = 0.033. The models for Cho/Cr and mI/Cr were not significant, nor were the effects for these metabolites on LF:HF ratio.
Table 3: Multiple linear regression models predicting ratio of low-frequency to high frequency heart rate variability by brain metabolite ratio

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  Discussion Top


Alterations in brain metabolite ratios are evident in older adults living with HIV and HTN. In this study, we sought to examine the regional specificity of those metabolite changes on the balance of resting autonomic tone women of post-menopausal age while accounting for disease status. Lower NAA to Cr ratios were found to predict higher ratio of sympathetic to parasympathetic tone after controlling for post-menopausal age, HTN and HIV status. These findings suggest that in older adult women decreased neuronal viability in the left anterior insula may an indicator of autonomic derangement evidenced by greater skew toward sympathetic arousal, independent of hormonal, HIV, or hypertensive status.

The findings of lower NAA ratios in persons diagnosed with HTN coincide with prior reports of lower NAA ratios among individuals with controlled and resistant HTN within frontal and bilateral anterior insula regions.[9],[10] Although this association for NAA and HTN status was not replicated in the HIV + group, here, greater Cho ratios were found in HIV + individuals endorsing HTN status. Prior studies examining brain metabolite markers of CVD risk in HIV have implicated posterior cingulate and caudate NAA values rather than Cho.[12] Another notable finding was the positive association between postmenopausal age and LF:HF ratio in the HIV + group. This finding appears to support prior literature showing a greater skew towards sympathetic arousal in older adult women, in part due to estrogen depletion during the postmenopausal period.[28],[29] Altogether, these findings suggest that NAA/Cr metabolite ratios within the left anterior insula may be markers for the sympathetic imbalance in post-menopausal women and that these effects appear to be more evident in aging HIV + women.

The exact neural mechanisms linking decreased NAA/Cr ratios to sympathetic imbalance are unclear, particularly within the context of HIV infection. A plausible explanation requires insight into the specific role of the left anterior insula in cardioautonomic regulation. Although the entirety of the central autonomic network, (i.e., medulla, hypothalamus, thalamus, somatosensory cortex, insular cortex, cingulate cortex, medial prefrontal cortex and amygdala) is thought to play a coordinated role in the regulation of HR, the left anterior insula is thought to play a critical role in the processing of interoceptive information via pulmonary stretch and baroreceptors of the lungs and heart; providing critical information for maintaining cardioautonomic tone.[30],[31],[32],[33] With regards to the effect of laterality it is important to note that in animal models of neurogenic HTN right insula activation and left anterior insula de-activation are observed during periods of sympathetic overarousal.[34],[35],[36] Similarly, neural stimulation, BP reactivity, and brain morphological studies also implicate structure and function of the left anterior insula in parasympathetic regulation with right insula playing a more integral role in sympathetic or pressor response.[19],[20],[37],[38],[39],[40],[41] Lesion studies also support the role of the left insula in the regulation of parasympathetic tone as damage to these areas have been linked to elevations in systolic BP, tachycardia as well as plasma norepinephrine spillover, indices of sympathetic imbalance.[42],[43],[44] Although the effects of small artery disease cannot be ruled out, our findings implicate neural integrity of the left anterior insula in cardio-autonomic regulation amongst postmenopausal women at risk for cerebrovascular diease.

Implications

Sympathetic overarousal and parasympathetic withdrawal are independent predictors of all-cause mortality associated with congestive heart failure, acute myocardial infarction, acute ischemic stroke, malignant cardiac arrhythmias, renal failure, chronic obstructive pulmonary disease, in addition to essential, masked, and chronic HTN. Depletion of estrogen during menopause has been linked to a rapid increase in CVD in adult women. Although we were not able to measure levels of estrogen, progesterone or other sex hormones, our findings beg the question of how menopause and aging may interact differently in HIV and HTN. What is known is that a dense array of estrogen receptors are located on nuclei throughout the brainstem, for example, nucleus of the solitary tract and dorsal motor nucleus of the vagus, that are involved in baroreceptor reflex and autonomic tone, and that many of these structures have dense afferent and efferent connections to the insula and other cardio-autonomic network structures though gamma-aminobutyric acid-ergic and Glutamatergic pathways [37],[45],[46],[47],[48],[49],[50],[51],[52] and their alteration during may associated with increased risk for CVD during the female reproductive period of estrogen withdrawal.[46],[53],[54] Future studies may need to explore brain metabolite changes to cardioautonomic network in the context of hormone replacement therapy.

Strengths and limitations

Several limitations of the present study should be considered. First, although we tout findings with regards to aging and cardio-autonomic function in HIV + women, the cross-sectional design of this study does not allow for an evaluation of causuality or disease etiology. Second, despite a relatively balanced distribution of HIV + and HTN + diagnoses, the study sample consisted of a relatively small number of participants, which may have led to an underestimation of the associations between brain metabolites and HRV. Third, HRV is very vulnerable to diurnal, postural, and psychological perturbations, however, we managed to obtain what we believe is a stable index of HRV by capturing beat-to-beat intervals gathered over 7 min in the supine position while the participant was at rest inside of the bore of the scanner, just prior to the MRS scan. As a result, these findings may not translate to indices of HRV derived from 24 h Holter monitor recordings. Nonetheless, short-order stationary HRV can provide very useful information about the autonomic function.[55] It is also important to note that presence of the metabolic syndrome can also impact cardio-autonomic regulation.[56] However, those women included in the study had not history or past treatment for cardiometabolic complications such as diabetes. Finally, it should be taken into consideration that although ratios of metabolite moieties regarding Cr are commonly reported in studies using MRS in HIV infection,[14],[15] Cr may be a less robust measure for comparing metabolite ratios in aging cohorts since they can vary across the brain in normal aging.[57] Thus, an alternative approach taken by some is to measure absolute values of each metabolite which would have gone undetected had the metabolites been measured solely as ratios.[58] Nonetheless, we took the current approach to be commensurate with the HTN literature as it pertains to metabolite concentrations in the anterior insula.


  Conclusions Top


Our data confirm an association between decreased NAA/Cr ratios and increased sympathetic imbalance suggesting neural integrity of the left anterior insula is relates to the balance of sympathetic to parasympathetic tone independent of age and chronic disease status, i.e., HIV + and HTN + diagnoses. We found that the strength of association was particularly strong in HIV + individuals. Moreover, older HIV + women are more likely to reveal this cardio-autonomic phenotype, thus supporting the clinical importance of spectral analysis of brain metabolites within central cardio autonomic brain structures such as the anterior insula. A more inclusive assessment of neuronal health of bilateral insula and other integral structures throughout the cardio-autonomic network may provide greater insight into the autonomic derangements and hypertensive risk observed in persons living with infectious chronic neurodegenerative and neuroinflammatory diseases such as HIV.

Financial support and sponsorship

1K01HL139722-01 (RM).

Conflicts of interest

There are no conflicts of interest.

 
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