HEADACHE & FACIAL PAIN SECTION

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1 Pain Medicine 2014; 15: Wiley Periodicals, Inc. HEADACHE & FACIAL PAIN SECTION Original Research Article An Association Between Migraines and Heart Anomalies True or False? A Heart Ultrasound Study Using ctte in Migraine Patients and Control Participants Izabela Domitrz, MD, PhD,* Grzegorz Styczynski, MD, PhD, Justyna Wilczko, MD, Malgorzata M. Marczewska, MD, Wojciech Domitrz, PhD, and Anna Kaminska, MD* *Departments of *Neurology, Internal Medicine, Hypertension and Angiology, Medical University of Warsaw, Warsaw; Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland Reprint requests to: Izabela Domitrz, MD, PhD, Department of Neurology, Medical University of Warsaw, 1a Banacha Street, Warsaw, Poland. Tel: ; Fax: ; izabela.domitrz@wum.edu.pl. Disclosure: There were no conflicts of interest and commercial relationships including grants, honoraria, speaker s lists, significant ownership, and/or support from pharmaceutical or other companies during our study. Abstract patients by routine and contrast transthoracic echocardiography. Subjects and Methods. We assessed the occurrence of PFO, ASA, and MVP in 96 patients with migraine without aura (87 females), in 62 patients with migraine with aura (41 females) and in 53 healthy persons (40 females). Results. In comparison with our control group, only the prevalence of PFO was statistically higher in patients with migraine (P ) and especially with aura (P ). We did not find any statistically significant differences between the occurrence of ASA or MVP in migraine and control groups. Conclusion. The results of our study raise the question of the heart s role in the mechanism of migraine attacks. If the occurrence of migraine with aura had been related to some heart abnormalities, the pathophysiology of migraine attacks may have some connection to some heart dysfunction. Resolving the association between migraine and comorbid cardiac conditions might shed light on the underlying mechanisms of migraines and even result in a different treatment strategy. However, we do not find any clear connection between PFP, ASA, and MVP, and migraine occurrence. Design. A migraine is a common neurological disorder that often coexists with other illnesses including heart abnormalities, such as patent foramen ovale (PFO), atrial septal aneurysm (ASA), and mitral valve prolapse (MVP). Objective. The aim of our study was to evaluate the occurrence of some heart abnormalities in migraine Key Words. Migraine; Cortical Spreading Depression; PFO; ASA; MVP; Heart Abnormalities Introduction A migraine is a common neurological disorder of uncertain pathogenesis clinically characterized by a distinctive 2156

2 Table 1 Demographic characteristics of the study population Patients M N MO N 5 96 MA N 5 62 Control group N 5 53 Sex M/F (M%) 30/128 (19%) 9/87 (9%) 21/41 (34%) 13/40 (25%) Mean Age 6 SD (Years) * * * * No difference between the study groups P > 0.05 M, MA vs the control group. M 5 all patients with migraine (MO 1 MA); MA 5 patients with migraine with aura; MO 5 patients with migraine without aura. headache and, in some patients, transient focal neurological symptoms of its aura. Prior studies have found that migraine occurred together with other illnesses. Delineating the comorbidities of migraine patients is important, because it can help to improve treatment strategies and elucidate the possible pathophysiology of migraine. The comorbid illnesses found in patients with migraines include stroke, subclinical vascular brain lesions, coronary heart disease, different heart abnormalities, among others [1]. A study by Bigal et al. evaluated the possible relationship between migraine and vascular finding a higher risk of myocardial infarction, ischemic stroke, and peripheral arterial disease [2]. Sch urks et al. confirmed that migraine with aura doubles the risk of cardiovascular diseases, including the risk of myocardial infarction [3]. It has also been suggested that a paradoxical cerebral embolism through a right-toleft blood shunt in the atrial chambers might be a possible cause of migraine attacks [4]. The paradoxical cerebral embolism during a Valsalva maneuver (VM) might evoke transient focal neurological symptoms. In fact a relationship between migraine and patent foramen ovale (PFO) and atrial septal aneurysm (ASA) has been previously suggested [5,6]. Rigatelli et al. in their study concerning PFO closure in migraine patients suggested that left atrial dysfunction probably does not contribute to the migraine itself but may play a role in the pathogenesis of aura symptoms [7]. In addition, a higher incidence of mitral valve prolapse (MVP) has been reported in patients with migraine [8,9]. The nature of the association between MVP and migraine remains uncertain. Arguments for a causal association are based upon reduced platelet survival and platelet aggregation in patients with MVP and the release of serotonin that has been implicated in the generation of migraine headaches [10]. It has further been suggested that genetically determined common endothelial-endocardial dysfunction may lead to both migraine and heart dysfunction [11,12]. Heart abnormalities, especially PFO, ASA, and MVP, have rarely been assessed in migraine patients. We did not find any studies evaluating these three abnormalities in the same patients. Therefore, we aimed to assess the occurrence of possible heart abnormalities in migraine patients and to discuss possible connections between these disorders and migraine without or with aura. Patients and Methods Migraine and the Heart The study group consisted of 158 consecutive migraine patients (all migraine patients M) treated in the Outpatient Headache Clinic, 96 of them with migraine without aura (MO) and 62 with migraine with typical aura (MA), as diagnosed according to the International Headache Society criteria, 3rd edition [13]. The demographic characteristics of the study population are presented in Table 1. The diagnosis of migraine headache was made by an experienced neurologist. The duration of the disease ranged from 1 to 33 years. The frequency of migraine attacks ranged between one attack per 1 week to one attack per 6 months (the mean frequency was one attack per 1 month). In all study subgroups, we performed routine transthoracic echocardiography (TTE) followed by TTE with contrast medium (ctte) during the VM. Patients were placed in the left lateral decubitus position with an intravenous cannula inserted in the antecubital fossa. Contrast medium was produced by the agitation of a small amount of air (1 ml), patient s blood (0.1 ml), and 9 ml of 0.9% saline using two 10 ml syringes connected to a three-way stopcock. Contrast was injected during the straining phase of the VM, and the apical four-chamber view was used for echocardiographic evaluation of contrast detection in the left heart chambers. The diagnosis of PFO was based on the presence of contrast (air bubbles) in the left atrium and ventricle within five cycles from the appearance of contrast in the right atrium. An ASA was diagnosed when the septum or its part was displaced at least 10 mm beyond the atrial septal plane. The diagnosis of PFO was based on the presence of contrast (air bubbles) in the left atrium within five cycles from the appearance of contrast in the right atrium. MVP was diagnosed when one or both mitral leaflets were displaced to the left atrium at least 2 mm above the plane of the mitral annulus. All the ultrasound examinations were performed by a single physician experienced in echocardiography. Our data on PFO, ASA, and MVP frequency was compared with the results of an age- and sex-matched control group (Table 1), which consisted of 53 healthy white persons without a history of any neurological and nor cardiovascular problems. Our control group consisted of 13 male and 40 female subjects, with a mean age of years (there was no difference between the ages of the study groups; P the control vs M). Controls were randomly selected from the hospital staff, 2157

3 Domitrz et al. Table 2 The prevalence of patent foramen ovale (PFO), atrial septal aneurysm (ASA), and prolapse of mitral valve (MVP) Study Groups PFO ASA MVP No Cardiac Abnormalities MO N 5 96 MA N 5 62 Control group N 5 53 students, and family of the study team or acquaintances of the study team. All of the individuals in the control group negated suffering from any headaches. They were screened by a general practitioner and then verified by an experienced neurologist. Statistical Analysis The statistical analysis of the data was performed using Statistica10 (Stat Soft Inc., Tulsa, OK, USA; Stat Soft Polska, Krakow, Poland). Statistical calculations were carried out using the Pearson chi-square test and the log-linear analysis with P <.05 used as a cutoff value. The study proposal was approved by the ethics committee of Medical University of Warsaw. Written informed consent was signed by all the participants. Results N 5 28 (30%)* N 5 15 (16%)* N 5 4 (4%)* N 5 62 (65%)* Mean age Mean age Mean age Mean age Male/female 6/22 Male/female 3/12 Male/female 1/3 Male/female 5/57 N 5 27 (43.5%) N 5 9 (14.5%)* N 5 5 (8%)* N 5 32 (52%) Mean age Mean age Mean age Mean age Male/female 8/19 Male/female 5/4 Male/female 3/2 Male/female 10/22 N 5 11 (21%) N 5 3 (6%)* N 5 2 (4%)* N 5 41 (77%) Mean age Mean age Mean age 21.5 Mean age Male/female 4/7 Male/female 1/2 Male/female 0/2 Male/female 8/33 *No difference between the study groups P > 0.05 MO, MA vs the control group. Statistically significant difference between the study groups P < 0.05 MA vs the control group. MA 5 patients with migraine with aura; MO 5 patients with migraine without aura. The results of PFO, ASA, and MVP frequency are presented in Table 2. The presence of PFO was found in 35% (55/158) of all the patients with migraine (M) compared with 21% of the control group. The Pearson chi-square test showed statistically significant differences between the study groups and the occurrence of PFO (v ; P ; df 5 2). However, in analyzing the migraine subgroups, the presence of PFO was found in 43.5% of the patients with MA, compared with 30% patients with MO (v ; P ; df 5 1), in contrast to 21% of the control group (v ; P ; df 5 1). This subanalysis showed a statistically significant difference in PFO frequency between MA patients and the control group, as confirmed by the Yates chi-square test (v ; P ) and the rang Spearman test (v ; P ). The presence of ASA was statistically insignificantly higher in the migraine group (24/158) as compared with the control group (15% vs 6%; v ; df 5 1; P ), without a difference between the MO and MA groups (P ) nor between the MO, MA, and the control groups (P and P ). Similarly, no difference was found in MVP prevalence (Table 2) in our study groups (v ; df 5 1; P ), again with no differences between the MO and MA subgroups (P ). Log-linear analysis performed for PFO, ASA, and MVP in all study subgroups (MO, MA, and the control group) showed a significant relationship between the occurrence of PFO and the type of the study subgroup (v ; df 5 2; P ). However, no significant differences were found for ASA and MVP in the study subgroups (for ASA v ; df 5 2; P and for MVP v ; df 5 2; P ). We found the conditions of PFO, ASA, MVP, and gender to be age-independent entities (multivariate analysis of variance F[4,188] , P ). Additionally, valve regurgitation was found in 23 25% of migraine patients and 33% of the control group (P to P ). Also, some degenerative changes of the mitral and/or tricuspid valves were identified in the migraine group, whereas such abnormalities were only rarely found in migraine patients who for many years had used ergotamine medications. There were no differences between the MO and MA subgroups (P 5 1). Discussion We found PFO to be present in 35% of all the patients with migraine but in 43.5% of the patients with MA. This result is similar to previously published findings [14]. The presence of PFO in our healthy control group was 21%, compared with an estimated 25% in the general 2158

4 population [15]. In our study, the presence of ASA was insignificantly higher in the migraine group as compared with the control group (15% vs 6%) and as compared with the general population (15% vs 3.2%) [16]. We did not find any difference in MVP prevalence between our patients and the control group, and the same goes for the general population [17]. The small degree of mitral and/or tricuspid valve regurgitation frequency was within the accepted limits of the general population. Regurgitation of the mitral and/or tricuspid valve is present in a high percentage of otherwise healthy individuals. Mitral regurgitation can be detected in 70 80%, whereas tricuspid regurgitation can be detected in 80 90%, of the general population [16]. To summarize the current study, we estimated the prevalence of PFO in M and especially MA patients as being higher than in our control group or in the general population. The prevalence of ASA and MVP were found to be similar in migraine patients, our control group, as well as the general population [15,16]. Some previous studies had reported a higher incidence of PFO [4,7], ASA [5,6], and MVP [8,9] in patients with migraine mainly with aura. However, none of these studies had screened for all three abnormalities in the same patients as we did, so this was a novel approach our study. It should be underlined that the only heart abnormality whose occurrence proved to be statistically higher in MA patients in our study was PFO. This finding is not new, whereas the prevalence of ASA and MVP in M patients is different than in previous studies. It is difficult to explain why there is not a statistically significant association between the occurrence of ASA, MVP, and MA, and this negative finding is in contrast to some earlier research, in which it was argued that ASA and MVP could lead to MA. Probably the relationship is connected with a purely endothelial-endocardial dysfunction, not lead migraine [11,12]. Support for this hypothesis is our additional result on the relationship between PFO, ASA, and MVP prevalence in the same patient. Also, the number of subjects in the analyzed groups, both in the migraine and the control groups, are relatively high. The large population of our study makes our results reliable and convincing, although the number of subjects in the control group is slightly lower than both migraine groups. However, our control group is younger than the MO group, but similar to the M group, also with respect to gender. Our difficulties in finding a properly matched control group revolved around issues in identifying completely healthy persons (negating any chronic illness, taking no medications, and without any headaches). This diagnosis was verified twice once by a general practitioner and a neurologist. Although our study did not show a statistically significance difference in ASA and MVP frequency in M, the results of earlier research allow us to discuss whether such a relationship might be of some clinical importance. Or perhaps the opposite is true heart abnormalities in M patients are completely meaningless in Migraine and the Heart migraine pathogenesis and treatment. There is a recently published study that negates the role of PFO in migraine [18]. The authors performed, similarly to our study, bubble ctte. The authors stated that the prevalence of moderate or large PFO was not associated with the presence of aura nor with the frequency of the migraine headache. Also Garg et al. [19] did not find any association between migraine headaches and the presence of PFO in their large case control study. The mechanism of migraine attacks in patients with heart abnormalities is still uncertain and unclear. It is probable that some changes in brain perfusion with transient hypoperfusion might provoke transient focal neurological symptoms, transient cerebral ischemia, and as a result of vascular changes postulated by some authors secondary cortical spreading depression. This abnormal perfusion hypothetically might be connected with paradoxical micromebolization as a trigger factor for subsequent processes. Micromebolization-driven cortical spreading depression as a mechanism connecting a migraine attack and heart abnormalities was recently suggested by Rigatelli et al. [20], who linked the microembolic hypothesis with cortical spreading depression in air microbubble-induced cerebral deoxygenation. On the other hand, one of the likely explanations for the coexistence of PFO, ASA, and migraine might be found in the results of the study by Yankovsky et al. [21], who suggested that altered atrial natriuretic peptide (ANP) plays a role in migraine headaches. ANP released from atrial myocytes is known to cause vasoconstriction and platelet aggregation. Thus, ANP might also play a role in the pathophysiology of migraine. Vidalon et al. [22] reported a decrease of fractional shortening, ejection fraction, and velocity of circumferential fiber shortening during a migraine attack. Recently, Ekici et al. [23] found diastolic dysfunction to be greater among migraine patients with a greater than 10-year history of migraine compared with the migraineurs with a history of less than 10 years. The authors concluded that cardiac diastolic dysfunction is associated with migraine occurrence. Understanding the association between migraine headaches and other comorbid health conditions is important in providing optimal patient care and explaining the underlying mechanisms of migraines. Recently, Schwarzmann et al. [24] summarized the current knowledge regarding the occurrence of PFO and its impact on migraine. 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