Higher Augmentation Index is Associated with Tension-Type Headache and Migraine in Middle-Aged/Older Humans with Obesity

Abstract

Objective

Obesity is a major risk factor for chronic daily headaches, including migraine and tension-type headache (TTH). Although migraine is associated with increased risk of cardiovascular diseases (CVD), a relation between TTH and CVD risk has not been established. It was hypothesized that higher carotid-femoral pulse wave velocity (CFPWV) and augmentation index (AI), measures of aortic stiffness and pressure wave reflection, respectively, and biomarkers of CVD risk, would be higher among adults with obesity and migraine or TTH compared with those with no headache.

Methods

Adults with obesity (n = 93; body mass index ≥30 kg/m²) who were between 40 and 75 years old with at least one additional CVD risk factor were enrolled. Subjects had CFPWV and AI assessed and a complete neurological exam for diagnosis of headache in the past 12 months.

Results

Adults with obesity and TTH (P = 0.018), but not migraine (P = 0.29), had significantly higher AI compared with those with no headache. When both CFPWV and AI were considered in a logistic regression model with migraine or TTH, only AI was associated with TTH (P = 0.008) and migraine (P = 0.032) but could not distinguish between the two headache phenotypes.

Conclusions

Increased aortic AI but not stiffness is associated with TTH and migraine among middle-aged/older adults with obesity and high CVD risk.

Introduction

Obesity is a major risk factor for the development of chronic daily headaches (1–3). In fact, in individuals with episodic headaches, adults with obesity are five times more likely to progress to chronic daily headaches than normal-weight adults (1). Moreover, the frequency and severity of chronic daily headaches is higher among adults with obesity. The two most common types of primary chronic daily headache (i.e., not attributed to an underlying condition) are tension-type headache (TTH) and migraine, with TTH being the most prevalent type (4,5). Although TTH and migraine are considered to be two distinct clinical disorders by the International Classification of Headache Disorders (ICHD-2) (6), they share some similarities and often coexist in the same individual. In this regard, Cady et al. (7,8) have advanced the “Convergence Hypothesis,” suggesting that migraine and TTH share a common pathophysiology and are in the same clinical spectrum. However, the mechanisms that contribute to the development of migraine or TTH remain incompletely understood.

Migraine is associated with increased risk of cardiovascular diseases (CVD) such as myocardial infarction and stroke (9–12), particularly in women with migraine with aura (11,12). In contrast, there are no reports of an association between CVD and TTH. Consistent with this, cerebrovascular and peripheral microvascular changes are known to occur in migraine; the etiology of TTH has been postulated to originate from myofascial tissues or from central mechanisms in the brain, but the pathophysiology of TTH remains poorly understood and vascular abnormalities have not been described (13–15).

Obesity is associated with migraine in multiple population studies (2,3,16), but evidence for an association between TTH and obesity is less clear (3). Obesity is also associated with increased aortic stiffness, assessed by carotid-femoral pulse wave velocity (CFPWV), a robust predictor of CVD morbidity and mortality in community-dwelling middle-aged and older adults (17–19). Interestingly, young nonobese adults with episodic migraine have increased aortic stiffness compared with age- and sex-matched control subjects, and migraineurs with aura have higher CFPWV than migraineurs without aura (20). Similarly, middle-aged migraineurs without CVD risk factors have higher brachial-ankle pulse wave velocity (PWV) compared with controls without migraine (21). Moreover, nonobese young adults with migraine also have higher aortic augmentation index (AI), a composite measure of the interaction between the forward and reflected pressure wave at the ascending aorta that can augment central systolic and pulse pressure and increase afterload (20,22–24). Thus, arterial stiffness and AI seem to be elevated in nonobese adults with migraine, but there are no data on whether arterial stiffness or AI are altered in TTH. Moreover, whether TTH or migraine headache is associated with increased aortic stiffness and AI among middle-aged/older adults who have obesity and high CVD risk is unknown.

Therefore, we hypothesized that middle-aged/older adults with obesity and with at least one other CVD risk factor and the presence of either migraine or TTH in the past 12 months would demonstrate higher aortic stiffness and AI compared with adults with obesity but without headache. Second, because migraine is associated with increased CVD risk, we hypothesized that adults with obesity and migraine would demonstrate higher aortic stiffness and AI than those with TTH and without any headache, thus providing a mechanistic link between migraine and increased CVD risk in this population.

Methods

Subjects

Adults with obesity (body mass index ≥30 kg/m² to be eligible) between ages 40 and 75 years who had at least one additional CVD risk factor (e.g., hypertension, hyperlipidemia, hyperglycemia, or metabolic syndrome) or who were being treated for a CVD risk factor (e.g., hypertension, hyperlipidemia) were enrolled in the study. All women were postmenopausal for at least 1 year. A total of eight women were on hormone replacement therapy. Three of these women were on transdermal patch and removed the patch 24 h prior to the experimental visit. Two of these women were on oral hormone replacement therapy and went off for 1 month prior to measurements. Three women used intravaginal cream or tablets for post-menopausal symptoms. The breakdown of hormone replacement therapy in each group is as follows: n = 4 in TTH group; n = 4 in the migraine group; and n = 0 in the no headache control group. Fifteen subjects were taking levothyroxine with doses ranging from 50 to 150 μg/day with the group breakdown as follows: n = 6 in TTH group; n = 7 in migraine group; and n = 2 in no headache control group. Subjects did not have clinical CVD as determined by lack of an atherosclerotic event and by a detailed medical history and physical exam by physician and resting 12-lead ECG. The subjects were recruited for this sub-study of the Clinical Trials.gov study NCT01351753. Subjects were sedentary or minimally recreationally active and were excluded if they indicated that they were doing any kind of a weight loss program or participating in a formal rigorous exercise program. Subjects were fasting for at least 8 h for study visits, and all visits were conducted at the University of Iowa Institute for Clinical and Translational Science Clinical Research Unit. The study was approved by the University of Iowa Institutional Review Board (IRB), and all subjects provided written informed consent in accordance with the University of Iowa IRB.

Headache and migraine assessment and classification

All subjects answered a detailed 17-item questionnaire adapted from the validated questionnaire from the American Migraine Prevalence and Prevention Study (25) (see Supporting Information Figure S1). This questionnaire assessed headache characteristics (associated symptoms, severity, frequency of headaches, age of onset, etc.), degree of headache-related disability, and treatments used. Subjects with a history of headaches and migraines had a complete neurological history and examination (including fundoscopic exam to rule out papilledema) conducted by a neurologist/headache specialist (A.R.) or a trained senior neurology resident (A.H.-T.). Following the administration of the questionnaire and neurological exam, diagnosis of headache type within the past 12 months was determined by the neurologist (A.R.) following ICHD-2 criteria (6).

In accordance with ICHD-2 criteria (6), subjects who had a diagnosis of migraine in this study included: migraine without aura, typical aura with migraine headache, typical aura without migraine headache, chronic migraine, probable migraine with aura, probable migraine without aura, probable chronic migraine, and pure menstrual migraine without aura. Subjects who had a diagnosis of TTH in the study included: infrequent or frequent episodic TTH with or without associated pericranial tenderness and chronic TTH with or without associated pericranial tenderness. Subjects with secondary headaches or other primary headache diagnoses were excluded.

Anthropometrics

Subjects were gowned, and after emptying their bladder, height (Holtain Limited, UK), weight (ST-Scale, Tronix, Wheaton, IL), and hip and waist circumference measurements were measured in triplicate and averaged.

Carotid-femoral pulse wave velocity

CFPWV, the “gold standard” measurement of aortic stiffness, was obtained noninvasively via applanation tonometry with the Sphygmocor (AtCor Medical, Itasca, IL) by sequentially recording pulse waveforms of the carotid and femoral arteries that were gated to the ECG to compute the pulse transit time (t) between the pulse sites (26). Path length (L) between two sites was calculated as distance from the suprasternal notch to carotid artery minus the distance from the suprasternal notch to the respective femoral or radial sites. CFPWV was computed as L/t. Measurements were made in duplicate and averaged, and quality of the data for individual subjects was in accordance with Sphygmocor recommendations.

Aortic AI

Aortic AI and central blood pressures were also obtained using the Sphygmocor (AtCor Medical) (26,27). Radial artery pressure waveforms were obtained via applanation tonometry of the radial artery pulse and calibrated to resting brachial artery systolic and diastolic blood pressures via standard sphygmomanometry. Aortic (central) systolic, diastolic, and pulse pressures were derived from an aortic blood pressure waveform synthesized using a generalized mathematical transfer function, which has been validated against invasive aortic pressure recordings in humans (28,29). Augmentation pressure is the difference between aortic systolic pressure and the pressure at the inflection point on the aortic pressure waveform from the arriving reflected wave at the ascending aorta and in general increases with higher aortic and peripheral artery stiffness, but is also influenced by nonstiffness factors, such as heart rate, height and left ventricular ejection dynamics. AI is calculated as the ratio of augmentation pressure divided by the aortic pulse pressure × 100% and corrected for a heart rate of 75 beats/min (AI@75bpm) (27). Pulse pressure amplification was calculated as the ratio of brachial to aortic pulse pressure and, in general, the magnitude of the amplification of the pulse pressure from the central to the peripheral circulation decreases as aortic stiffness and pulse pressure are increased (in the absence of changes in peripheral artery stiffness). An average of two recordings were performed and averaged, and only data with a quality index of 80 or higher were accepted.

Laboratory tests

Blood and urine samples were collected and analyzed in the Core Laboratory of the University of Iowa Hospitals and Clinics Pathology Department. Laboratory blood tests were performed for total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, glucose, creatinine, high-sensitivity C-reactive protein, and insulin.

Statistical analysis

All data are expressed as mean ± standard deviation (SD). Subject variables were compared between those with current TTH or migraine and those without TTH and migraine using one-way ANOVA. A multinomial logistic regression model was fitted to assess the association of CFPWV and AI corrected for heart rate of 75 beats/min with presence of TTH or migraine in the past 12 months. The outcome categories of the multinomial dependent variable were presence of migraine, TTH, and no migraine/TTH, with the no migraine/TTH as the reference category. An alpha level of P < 0.05 was required for significance.

Results

A total of 133 subjects were screened for this study from March 2011 until August 2013. Of the 133 subjects originally screened for this cross-sectional study, 40 were excluded as a result of incomplete answers to survey or headache attributed to increased cerebrospinal fluid pressure. Headaches diagnosed as non-TTH or non-migraine, such as medication overuse, caffeine withdrawal, rhinosinusitis, temporomandibular joint disorder, or head or facial pain attributed to herpes zoster were excluded from the analysis. A total of 93 subjects were included in the study, with a total of 39 being classified as having migraine, 25 with TTH, and 29 with no current migraine or TTH within the past 12 months (Table 1). However, reliable radial, carotid, or femoral waveforms were not obtainable in 16 subjects with obesity, so final analysis was performed on 77 subjects (migraine n = 31; TTH n = 22; no headache/migraine n = 24).

TABLE 1.

Subject characteristics among middle-aged/older adults with obesity and no migraine/tension-type headache (TTH), migraine, or TTH in the past 12 months

	No TTH or migraine	Migraine	TTH	P-value
n	29	39	25
Age (years)	54 ± 7	53 ± 8	57 ± 6	0.18
Female sex, n (%)	14 (48)	26 (67)	18 (72)	0.15
Weight (kg)	108 ± 13	108 ± 21	102 ± 12	0.31
Body mass index (kg/m2)	37 ± 5	38 ± 6	37 ± 4	0.79
Waist circumference (cm)	118 ± 9	119 ± 15	120 ± 17	0.90
Hip circumference (cm)	121 ± 14	125 ± 11	124 ± 12	0.32
Heart rate beats/min	64 ± 7	64 ± 9	65 ± 13	0.83
Antihypertensive medications, n (%)	13 (52)	25 (66)	15 (60)	0.55
Antihyperlipidemia medications, n (%)	8 (32)	13 (34)	10 (40)	0.83
Total cholesterol (mg/dl)	203 ± 44	209 ± 41	188 ± 34	0.14
LDL-cholesterol (mg/dl)	118 ± 34	120 ± 38	113 ± 35	0.76
HDL-cholesterol (mg/dl)	57 ± 28	59 ± 21	55 ± 18	0.76
Triglycerides (mg/dl)	108 ± 96	134 ± 77	119 ± 40	0.41
Glucose (mg/dl)	99 ± 12	101 ± 29	98 ± 12	0.87
Insulin (μU/ml)	16.1 ± 11.0	14.9 ± 11	14.7 ± 8.1	0.86
Creatinine (mg/dl)	0.89 ± 0.16	0.88 ± 0.18	0.85 ± 0.18	0.75
C-reactive protein (mg/l)	3.0 ± 3.4	3.2 ± 3.0	3.7 ± 3.4	0.79

Data are mean ± SD. LDL, low-density lipoprotein; HDL, high-density lipoprotein.

There were no significant differences in any subject characteristics between those with no TTH/migraine, migraine or TTH (Table 1). Similarly, there was no significant difference in brachial systolic, diastolic, and mean blood pressure, CFPWV, or pulse pressure amplification between subjects with no current TTH/migraine, migraine, or TTH (Table 2). Lastly, despite no difference in CFPWV between groups, adults with obesity and TTH demonstrated significantly higher aortic AI compared with those with migraine or no headache, suggesting a larger reflection intensity or early return of the wave reflection from the periphery at the ascending aorta in this group (Figure 1).

TABLE 2.

Peripheral and central blood pressure and pulse wave velocity among middle-aged/older adults with obesity and no migraine or tension-type headache (TTH), migraine, or TTH in the past 12 months

	No TTH or migraine	Migraine	TTH	P-value
Brachial systolic BP (mmHg)	127 ± 11	133 ± 14	132 ± 15	0.33
Brachial diastolic BP (mmHg)	75 ± 9	75 ± 9	74 ± 10	0.90
Brachial pulse pressure (mmHg)	53 ± 14	58 ± 13	59 ± 13	0.26
Brachial mean pressure (mmHg)	94 ± 7	96 ± 10	96 ± 12	0.58
Aortic systolic BP (mmHg)	116 ± 9	123 ± 16	123 ± 16	0.15
Aortic pulse pressure (mmHg)	40 ± 11	46 ± 14	47 ± 13	0.11
CFPWV (m/s)	9.2 ± 1.7	8.4 ± 2.9	8.7 ± 2.0	0.47
Pulse pressure amplification	1.33 ± 1.2	1.27 ± 1.6	1.25 ± 1.4	0.19

Data are mean ± SD. BP, blood pressure; CFPWV, carotid-femoral pulse wave velocity

Figure 1.

Aortic augmentation index corrected for heart rate of 75 beats/min among middle-aged/older adults with obesity and no tension-type headache (TTH)/migraine, migraine, or TTH in the past 12 months. *P < 0.05 vs. no current migraine/TTH.

To answer the question as to whether elevated AI or CFPWV predicted the presence specifically of either TTH or migraine based on the ICHD-2 criteria (6), we conducted a multinomial logistic regression analysis. When we considered both AI and CFPWV together in the model for migraine and TTH, AI, but not CFPWV, was significantly associated with presence of both TTH and migraine with similar effect of AI on both TTH and migraine (Table 3). For a +5 unit (i.e., %) increase in AI, the odds ratio (relative to the no TTH or migraine control group) of TTH was 1.70 (95% CI: 1.15–2.52) and of migraine was 1.46 (1.03–2.08). Thus, these data suggest that elevated AI, but not CFPWV, was independently associated with the presence of either migraine or TTH but could not distinguish between the two headache phenotypes.

TABLE 3.

Parameter estimates of multinomial logistic regression model for the dependent variable of tension-type headache (TTH) or migraine with CFPWV and augmentation index@75bpm as independent variables

Parameter	Migraine (vs. no TTH/migraine)				TTH (vs. no TTH/migraine)
	Estimate	Standard error	Odds ratioa (95% CI)	P-value	Estimate	Standard error	Odds ratioa (95% CI)	P-value
Model 1
Intercept	1.674	1.202			0.696	1.327
CFPWV	−0.160	0.132	0.72 (0.43–1.22)	0.223	−0.094	1.444	0.83 (0.47–1.46)	0.517
Model 2
Intercept	−0.888	0.702			−2.086	0.874
AI@HR75	0.058	0.033	1.34 (0.97–1.84)	0.075	0.092	0.038	1.58 (1.09–2.30)	0.015
Model 3
Intercept	0.926	0.926			−0.628	1.506
CFPWV	−0.245	0.144	0.61 (0.35–1.07)	0.087	−0.194	0.160	0.68 (0.36–1.27)	0.226
AI@HR75	0.076	0.036	1.46 (1.03–2.08)	0.032	0.106	0.040	1.70 (1.15–2.52)	0.008

^aOdds ratio is for a +2 difference in CFPWV and +5 difference in AI@HR75.

CFPWV, carotid-femoral pulse wave velocity; AI@HR75, augmentation index corrected for heart rate of 75bpm.

Discussion

This study has four primary findings. First, middle-aged/older adults with obesity at high risk for CVD and with TTH in the past 12 months demonstrated higher aortic AI compared with adults with obesity and no headache or migraine that could not be explained by differences in conventional CVD risk factors. Contrary to our hypothesis, we found that aortic stiffness was not higher among middle-aged/older adults with obesity and migraine but was also not higher in those with TTH compared with those with no headache in the past 12 months. Second, although aortic AI was selectively higher in adults with obesity and TTH compared with no headache or with migraine, in logistic regression analysis, higher aortic AI was associated with both TTH and migraine but could not distinguish between the two headache phenotypes. Taken together, these data suggest that AI, but not aortic stiffness or blood pressure, is more closely associated with the presence of TTH and migraine in the past year among middle-aged/older adults with obesity and at elevated CVD risk.

Migraine is associated with increased risk of myocardial infarction and stroke (9–12). Consistent with this, patients having unilateral migraine attacks were shown to have widespread peripheral arterial constriction in radial arteries during migraine (30) and increased coronary microvascular dysfunction with migraine incidence (31). Thus, a systemic impairment in microvascular function seems to be present in migraine sufferers, providing a potential mechanistic link between migraine and increased CVD risk. However, recent studies demonstrate that healthy adults with migraine demonstrated higher aortic stiffness and/or AI, that are both independent predictors of CVD events. Thus, alterations in large artery stiffness and central artery hemodynamics, rather than microvascular dysfunction, may be another vascular mechanism by which migraine confers increased CVD risk. Indeed, a previous case–control study in young adults without obesity or CVD risk factors who experienced episodic migraine demonstrated elevated CFPWV when compared with non-migraineurs even after adjusting for conventional CVD risk factors (20). Similarly, middle-aged normal-weight migraineurs at low CVD risk demonstrated higher brachial-ankle PWV, a composite measure of aortic and muscular upper and lower limb artery stiffness, compared with nonmigraineur controls (21). The results of these studies differ with our study in that we did not find significant differences in CFPWV among adults with obesity with vs. without any current headache, as well as between those with current migraine or TTH. The divergent results are likely a result of differences in the populations studied. For example, we studied middle-aged/older adults who had obesity and at least one additional CVD risk factor, and about one-half of our subjects were taking antihypertensive medications and one-third were on antidyslipidemia medications although the headache groups did not differ in medications. In contrast, Schillaci et al. (20) studied young adults and excluded those with hypertension, dyslipidemia, obesity, and, importantly, subjects with “chronic” migraine, whereas we included subjects with both “episodic” and “chronic” migraine. In agreement with our study, Stam et al. (32) found no difference in CFPWV among nonobese, middle-aged adults with vs. without migraine in a large nested case–control study. Taken together, these studies suggest that alterations in large artery stiffness and wave reflection in migraineurs may differ depending on the age, CVD risk burden, and use of medications in the population studied, and whether subjects with episodic vs. chronic symptoms are included.

Although some studies have reported that headaches are positively associated with hypertension (33,34), several large cross-sectional and longitudinal studies demonstrate a clear inverse relation between blood pressure and migraine and/or TTH, suggesting that headache is paradoxically associated with lower, not higher, blood pressure (35,36). In this study, there was no significant difference in brachial artery systolic or diastolic blood pressure between the three groups. However, adults with obesity and TTH had significantly higher aortic AI compared with migraineurs and no headache controls, suggesting that central augmented pressure at the ascending aorta may be either: (1) causal in the development of TTH in adults with obesity, (2) or alternatively, that TTH in obesity somehow causes elevated AI perhaps through altered wave reflection intensity or timing from elevated peripheral arterial tone.

Moreover, in logistic regression analysis when AI and CFPWV were considered separately with both TTH and migraine together in the model (Table 3), only AI predicted TTH (Table 3). However, when we investigated whether AI was more closely associated with the presence of TTH or migraine, higher AI was associated with both TTH and migraine but could not distinguish between the two headache phenotypes (Table 3).

The mechanisms by which AI might contribute to TTH or migraine in the absence of higher aortic stiffness are unknown, but it is also possible that headache may mediate increased central pressure wave reflection from the periphery. For example, we speculate that chronic headache symptoms could lead to augmented wave reflection from repetitive sympathetic activation and elevation in peripheral arterial tone (without changes in aortic stiffness), resulting in higher afterload and subsequent increased CVD risk in chronic headache disorder. Alternatively, another interpretation of our data is that elevated wave reflection via elevated tone from local vascular mechanisms, such as reduced nitric oxide-dependent endothelial function, contributes to the pathogenesis of headaches in obesity through deeper penetration of pulsatile pressure into the microcirculation of the brain, leading to episodic or chronic headache pain. However, given that our results are associations, the directions of the pathogenesis of headache disorder in obesity related to AI cannot be determined. Nevertheless, elevated AI and related parameters are associated with CVD events in several studies (37,38), indicating that adults with obesity and migraine or TTH may be at heightened CVD risk compared with adults with obesity but without headache.

Limitations of this study include the cross-sectional design, which does not allow conclusions about the cause and effect relation between AI and presence of TTH or migraine. However, the study has several strengths, including the well-characterized CVD risk factors of the cohort of adults with obesity, the diagnosis of headache made by a headache specialist after interview and examination of subjects, and the use of logistic regression analysis to test the hypothesis that aortic stiffness and wave reflection hemodynamics are associated with the presence of absence of migraine or TTH. We also lacked a headache control group without obesity, but our goal was to determine whether elevated aortic stiffness or AI was higher among adults with obesity and migraine or TTH, not in adults with vs. without obesity. The generalized transfer function and radial artery tonometry to derive central blood pressure and AI has not been validated specifically in adults with obesity at high CVD risk, and one study reported that the transfer function performs less well at higher blood pressures (39). However, Sharman et al. (40) reported very reliable estimates of central pressure at high blood pressures during exercise when compared with invasively recorded pressures. Furthermore, AI is a complex hemodynamic parameter involving the interaction between the forward and reflected pressure wave in part from the degree of impedance mismatch between central and peripheral arterial stiffness. It is also affected by non-stiffness and -wave reflection characteristics such as systolic ejection duration, cardiac contractile dynamics, heart rate, and height. Thus, the precise hemodynamic component that is driving the elevated AI in adults with obesity and headache is unknown.

In conclusion, this is the first study to report that aortic AI, and not CFPWV, is associated with presence of TTH and migraine among middle-aged/older adults with obesity at high CVD risk. Although higher AI was associated with the presence of TTH in unadjusted analysis, it was unable to distinguish between the two headache phenotypes in multiple logistic regression. Larger longitudinal studies are needed to explore the mechanisms by which TTH and migraine are associated with greater AI in human obesity. Better understanding of these mechanisms may shed light on the neuro- and/or vascular biology of TTH and migraine, potentially reveal novel therapeutic targets for headache disorder in adults with obesity, and possibly reduce CVD risk.