Article ID: WMC004975 ISSN 2046-1690

Claustrophobia, Panic Attacks and Caffeine Intolerance may NOT be associated with Diastolic Dysfunction: A Pre-Echocardiogram Questionnaire-Based Pilot Study

Peer review status: No

Corresponding Author: Dr. Deepak Gupta, Anesthesiologist, Wayne State University, 48201 - United States of America

Submitting Author: Dr. Deepak Gupta, Anesthesiologist, Wayne State University, 48201 - United States of America

Other Authors: Dr. Anupama Kottam, Cardiologist, Wayne State University - United States of America Dr. Sarwan Kumar, Internist, Wayne State University - United States of America Dr. Ashish Mazumdar, Former Research Assistant, Detroit Medical Center - United States of America

Article ID: WMC004975 Article Type: My opinion Submitted on:12-Sep-2015, 05:04:16 AM GMT Published on: 14-Sep-2015, 09:27:26 AM GMT Article URL: http://www.webmedcentral.com/article_view/4975 Subject Categories:CARDIOLOGY Keywords:Claustrophobia, Panic Attacks, Caffeine Intolerance, Diastolic Dysfunction, Echocardiogram How to cite the article:Gupta D, Kottam A, Kumar S, Mazumdar A. Claustrophobia, Panic Attacks and Caffeine Intolerance may NOT be associated with Diastolic Dysfunction: A Pre-Echocardiogram Questionnaire-Based Pilot Study. WebmedCentral CARDIOLOGY 2015;6(9):WMC004975 Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source(s) of Funding: None

Competing Interests: None

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Additional Files: Appendix A Table 1 Table 2 Table 3 Table 4

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Claustrophobia, Panic Attacks and Caffeine Intolerance may NOT be associated with Diastolic Dysfunction: A Pre-Echocardiogram Questionnaire-Based Pilot Study

Author(s): Gupta D, Kottam A, Kumar S, Mazumdar A

Abstract attacks and caffeine intolerance may NOT be associated with diastolic dysfunction. Introduction Background: Diastolic heart dysfunction may explain the enigmatic pathophysiology of panic attacks and related disorders like claustrophobia, Diastolic heart dysfunction may explain the enigmatic subjective/objective intolerance of heated enclosed pathophysiology of panic attacks and related disorders environments and caffeine intolerance/allergy that can like claustrophobia, subjective/objective intolerance of be sometimes indistinguishable from panic attacks heated enclosed environments and caffeine symptomatically. intolerance/allergy that can be sometimes Objectives: To investigate whether clinical history of indistinguishable from panic attacks symptomatically. panic attacks-claustrophobia-caffeine intolerance is Diastolic dysfunction includes impaired isovolumetric more common in patients with undiagnosed diastolic ventricular relaxation, poorly compliant left ventricles dysfunction who present for their outpatient and higher filling pressures that when transmitted to echocardiogram tests. pulmonary vasculature can potentially mimic panic Materials and Methods: Consenting adult outpatients attacks symptomatically. Eventually, decreased stroke 1 who presented for their scheduled outpatient volume/cardiac output can cause effort intolerance. echocardiogram or stress echocardiogram at our Based on above-mentioned our hypothesis/projected University Hospital based Echocardiography understanding, the purpose of the current study was to Laboratory were asked to complete a questionnaire investigate whether clinical history of panic attacks related to the clinical history of panic attacks, and/or claustrophobia and/or caffeine intolerance is claustrophobia and caffeine intolerance. Spearman more common in patients with undiagnosed diastolic Rank Correlation and Partial Correlation Coefficients dysfunction who present for their outpatient were used to correlate echocardiographic diastolic echocardiogram tests. function grades with claustrophobia, panic attacks and Materials and Methods caffeine intolerance based extracted (CP/CI/CPCI ) After institutional review board approval for scores. prospective questionnaire-based study, a written and Results: Due to very small (n=40) pilot results (despite informed consent for inclusion in the study was taken planned large-scale study at outset), we were only from the outpatients aged 18 years and above who able to infer that: (a) there was only 75% inter-rater presented for their scheduled outpatient concordance in regards to diagnosing diastolic heart echocardiogram or stress echocardiogram at our function on echocardiogram; (b) patients with diastolic University Hospital based Echocardiography heart dysfunction were significantly older; (c) 75% Laboratory. Inpatients, pregnant patients and lactating patients in our study pool were females; (d) diastolic patients with recent delivery within last 6 months were heart dysfunction was prevalent in 45% patients; (e) excluded from the study. After the registration process there was very little (if any) clinical significance of for echocardiogram, the patients were approached for CP/CI/CPCI scores in regards to predicting diastolic their consent to participate in the study. They were dysfunction grading; and (f) claustrophobia-panic asked to complete a questionnaire related to the attacks vs. caffeine-intolerance/allergy did not co-exist clinical history of panic attacks, claustrophobia and as co-morbidities in our set of patients. caffeine intolerance while they were waiting for Conclusion: Per our pre-echocardiogram scheduled echocardiograms. Subsequently patients questionnaire-based pilot study, claustrophobia, panic underwent their scheduled echocardiograms or stress

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echocardiograms. Cardiac sonographers acquiring the confounding factor even though 75% among the study and echocardiogram-reading clinical analyzed patients were females. Prevalence of cardiologists were blinded to the patients’ responses abnormal diastolic function grade was 45% during our to the study questionnaires. Subsequently, the study. Sensitivity, specificity, positive predictive value echocardiogram results were accessed and diastolic and negative predictive value for Claustrophobia-Panic function in those echocardiograms were re-assessed (CP) Scale/Score, Caffeine-Intolerance (CI) and confirmed by the researchers including a research Scale/Score and cardiologist who was blinded to the Claustrophobia-Panic-Caffeine-Intolerance (CPCI) echocardiographers' readings-results as well as to the Scale/Score were low most likely due to low power patient’s responses to the study questionnaire. (sensitivity), high type I error (1-specificity) and high Statistical Analysis type II error (1-sensitivity) except for 73% specificity of CI Scale/Score and 67% sensitivity of CPCI Despite initially planned larger sample size, the study Scale/Score in regards to diastolic function grading. was only completed, then closed and analyzed for 43 Similarly likelihood ratios (both positive and negative) consenting patients as a pilot. Additionally, collected weighted for prevalence were close to or equal to 1 responses/data of four page long questionnaires per that meant little clinical significance of CP/CI/CPCI patient as well as two page long echocardiogram scores in regards to predicting diastolic dysfunction parameters per patient (Appendix A) were respectively grading. reformatted (only for analysis) into 8-point questions-based Extracted Scores (Table 1) and As far as Spearman correlation coefficients were 4-point diastolic function grade per American Society concerned (Table 4), patient's age showed strong of Echocardiography (Table 2).2 The data was positive correlation with echocardiogram based analyzed and compared with Spearman Rank diastolic function grading (r=0.66; P< 0.01). Similarly, Correlation and Partial Correlation Coefficients to CP scores and CI scores had significant positive deduce whether there was any correlation of diastolic correlation with CPCI scores (P< 0.01) because CPCI function grades (Table 2) with claustrophobia, panic scores are numerical sum total of CP scores and CI attacks and caffeine intolerance based scores (Table scores. These significant correlations persisted and 1). The proportions were compared with Chi Square even became stronger for CP:CPCI and CI:CPCI test (Fisher Exact Tests). Means were compared with correlations when effects of other variables were Analysis of Variance (ANOVA). A p value of < 0.05 controlled in the 6x6 partial correlation matrix (Table was considered significant. 4). Moreover, after controlling for other variables, a strong negative partial correlation appeared between Results CP scores and CI scores (r=-0.9; P< 0.01) suggesting In these pilot results for 43 patients, two patients were the non-existence of claustrophobia-panic and excluded as after completion of questionnaires, they caffeine-intolerance as co-existing co-morbidities in did not undergo their scheduled echocardiograms due our set of patients. to clinical reasons unrelated to our research; and another patient was excluded as diastolic dysfunction Discussion could not be graded due to underlying mitral stenosis. Among the remaining 40 patients whose data were finally analyzed as above-mentioned by the researchers, diastolic function had not been A panic attack by definition is a conglomerate of at graded/reported by clinical cardiologist in four patients least four symptoms among the following: palpitations, and among remaining 36 patients, there was 75% heart pounding or a rapid pulse, sweating, trembling or inter-rater concordance in regards to diastolic function shaking, breathing problems, such as shortness of grading between clinical cardiologist and research breath or feeling smothered, feeling of choking, chest cardiologist while in the remaining 25% patients, pain or chest discomfort, abdominal discomfort, upset research cardiologist's blinded assessment resulted in stomach or nausea, feeling faint, dizzy, light-headed or upgrading the diastolic dysfunction scores as unsteady on your feet, feeling unreal or detached from compared to clinical cardiologist's report. yourself, of losing control, fear of dying, In regards to 40 patients finally analyzed (Table 3), numbness or tingling in arms, legs or other parts of the patients were significantly (P< 0.01) older in age if the body, chills or hot flushes etc. Panic attack assessed diastolic function grade was abnormal symptomatology is often indistinguishable from cardiac (non-zero) however patient's sex was not a pathology symptomatology that can include chest pain, shortness of breath, stomach discomfort, dizziness,

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and a sense of impending death. While panic attacks presentations and hence besides avoiding the themselves may not be deadly, patients with panic precipitating factors, various medications have been disorder have reduced heart-rate variability (HRV) that tried for these disorders. Calcium channel blockers increases risk for cardiac arrhythmia and sudden (CCBs) like verapamil, diltiazem and nimodipine, have death.3, 4 Low baseline high frequency HRV may reflect been tried for disorders but evidence is very inflexibility of autonomic nervous system in anxiety weak.15Similarly, pregabalin that exerts alteration in disorders involving hypervigilance with perceptive voltage-sensitive calcium channels (mechanism difficulty to disengage from perceived threats.5 dissimilar to cardiac CCBs) have shown some Eventually underperforming parasympathetic nervous prominence in management of .16, 17 system and overactive sympathetic nervous system Similarly, though beta blockers decrease heart rate result in long term low HRV at baseline.6 Similarly, and systolic blood pressure, the subjective anxiety has although initial reports of correlation of not responded to beta blockers and may actually and mitral valve prolapse (MVP) have not been worsen with propranolol.18 substantiated as cause-and-effect relationship, the Therefore, our assumption was to explore elusive unknown mechanism should not deter the (isolated/co-existent) diastolic heart dysfunction appreciation of high rates for co-existence of both explaining out above-mentioned enigmatic 7 disorders. pathophysiology: (a) poor correlation of MVP and CLAUSTROPHOBIA Panic attacks in previous echocardiogram based trials Claustrophobia, typically classified as an anxiety presumably due to incomplete investigations about the disorder, often presents as panic attack, resulting from diastolic parameters in those trials; (b) low baseline many situations or stimuli, including but not limited to HRV as a presumable explanation for fragility of the elevators crowded to capacity, windowless rooms, and diastolic heart parameters and presentation as acute even tight-necked clothing. This can be dysfunction/failure in response to sudden surge in indistinguishable from the symptomatology of anxiety-related sympathetic activity; and (c) subjective/objective intolerance of heated enclosed incomplete response of panic attacks to beta-blockers environments especially during winters requiring fans alone presumably projecting that besides heart rate in those enclosed environments as similar to the control, these patients may also need angiotensin II subjective anti-distress effects of fans used inside the receptor blockers, angiotensin-converting-enzyme magnetic resonance imaging scanners.8 When inhibitors and calcium channel blockers to normalize 19 confined, claustrophobics may present with sweating, the stiff and poorly relaxed diastolic hearts. However, accelerated heart rate, increased blood pressure, due to very small (n=40) pilot results (despite planned hyperventilation, shaking, panic attacks, large-scale study at outset), we were able to infer only light-headedness, nausea, fainting, of actual the following: (a) there was only 75% inter-rater harm or illness. Though claustrophobia is a prevalent concordance in regards to diagnosing diastolic heart with two major fear(s) of restriction and function on echocardiogram; (b) patients with diastolic suffocation, the majority of claustrophobics are not heart dysfunction were significantly older; (c) 75% receiving treatment for it.9, 10 patients in our study pool were females; (d) diastolic heart dysfunction was prevalent in 45% patients; (e) CAFFINE INTOLERANCE there was very little (if any) clinical significance of Although almost all of American population ingests CP/CI/CPCI scores in regards to predicting diastolic coffee regularly, a fraction of population is dysfunction grading; and (f) claustrophobia-panic allergic/intolerant to caffeine.11, 12 Caffeine allergy attacks vs. caffeine-intolerance/allergy did not co-exist (intolerance) presents with heart, breathing and as co-morbidities in our set of patients. anxiety symptoms besides rashes, and facial swelling. Our study had many limitations. Logistically the Study in healthy volunteers found decreased contemplated larger study was not completed that myocardial flow reserve (exercise-induced) with could have (with strong statistical power) validated or 200mg caffeine.13 Additionally, caffeine related calcium refuted the current pilot results. The current pilot influx and subsequent reversible ‘contracture’ results did not differentiate isolated vs. co-existent (incomplete myocardial relaxation) accentuates left diastolic heart dysfunction wherein cardiac ventricular filling pressure and diastolic pressure co-morbidities might have confounded our results during myocardial ischemic episodes in the setting of (type I and II errors). The only positive findings were pacing-induced tachycardia.14 the obvious/natural positive correlation of increased This plethora of panic disorders has overlapping stiffening of hearts with aging of patients, and

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selection bias related high prevalence of diastolic (CA): Shellock R & D Services, Inc. heart dysfunction in patients (not healthy volunteers) MRISAFETY.COM; 2015 [updated 2015; cited 2015 July 28]. Available from: presenting for their scheduled outpatient http://www.mrisafety.com/SafetyInfov.asp?SafetyI echocardiograms. The pilot results may need further nfoID=253 explorations for the validity of 9. Ost LG. The claustrophobia scale: a psychometric extracted/deduced/analyzed CP/CI/CPCI scores in evaluation. Behav Res Ther. 2007 May;45(5):1053-64. future studies in healthy volunteers among whom only 10. Rachman S, Taylor S. Analyses of claustrophobia. allowable symptomatology will include variable J Anxiety Disord. 1993 Oct-Dec;7(4):281-91. non-zero numerical scoring per CP/CI/CPCI scores 11. Moawad H. Signs and symptoms of caffeine (Table 1) and variably graded isolated diastolic heart intolerance [Internet] c2015. Santa Monica (CA): dysfunctions (Table 2) on their otherwise normal Demand Media, Inc. LIVESTRONG.COM; 2014 February 7 [updated 2014 February 7; cited 2015 echocardiograms. July 28]. Available from: Conclusion http://www.livestrong.com/caffeine-allergy/ 12. Dager SR, Layton ME, Strauss W, Richards TL, Per our pre-echocardiogram questionnaire-based pilot Heide A, Friedman SD, Artru AA, Hayes CE, study, claustrophobia, panic attacks and caffeine Posse S. Human brain metabolic response to intolerance may NOT be associated with diastolic caffeine and the effects of tolerance. Am J . 1999 Feb;156(2):229-37. dysfunction but this may NOT preclude exploring this 13. Namdar M, Koepfli P, Grathwohl R, Siegrist PT, aspect in future with larger studies that can Klainguti M, Schepis T, Delaloye R, Wyss CA, validate/refute the results after correcting the poor Fleischmann SP, Gaemperli O, Kaufmann PA. statistical power and type I&II errors of the current pilot. Caffeine decreases exercise-induced myocardial flow reserve. J Am Coll Cardiol. 2006 Jan References 17;47(2):405-10. 14. Paulus WJ, Serizawa T, Grossman W.Altered left ventricular diastolic properties during pacing-induced ischemia in dogs with coronary stenoses. Potentiation by caffeine. Circ Res. 1982 1. Satpathy C, Mishra TK, Satpathy R, Satpathy HK, Feb;50(2):218-27. Barone E. Diagnosis and management of diastolic 15. Balon R, Ramesh C. Calcium channel blockers for dysfunction and heart failure. Am Fam Physician. anxiety disorders? Ann Clin Psychiatry. 1996 2006 Mar 1;73(5):841-6. Dec;8(4):215-20. 2. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, 16. Schneier FR. Pharmacotherapy of Oh JK, Smiseth OA, Waggoner AD, Flachskampf disorder. Expert Opin Pharmacother. 2011 FA, Pellikka PA, Evangelista A. Mar;12(4):615-25. Recommendations for the evaluation of left 17. Fink K, Dooley DJ, Meder WP, Suman-Chauhan N, ventricular diastolic function by echocardiography. Duffy S, Clusmann H, Göthert M. Inhibition of J Am Soc Echocardiogr. 2009 Feb;22(2):107-33. neuronal Ca(2+) influx by gabapentin and 3. Lombardi F, Mäkikallio TH, Myerburg RJ, Huikuri pregabalin in the human neocortex. HV. Sudden cardiac death: role of heart rate Neuropharmacology. 2002 Feb;42(2):229-36. variability to identify patients at risk. Cardiovasc 18. Fagerström KO, Hugdahl K, Lundström N. Effect Res. 2001 May;50(2):210-7. of beta-receptor blockade on anxiety with 4. Routledge HC, Chowdhary S, Townend JN. Heart reference to the three-systems model of phobic rate variability--a therapeutic target?J Clin Pharm behavior. Neuropsychobiology. 1985;13(4):187-93. Ther. 2002 Apr;27(2):85-92. 19. Zile MR, Gaasch WH. Treatment and prognosis of 5. Pittig A, Arch JJ, Lam CW, Craske MG. Heart rate diastolic heart failure. In: UpToDate, Colucci WS and heart rate variability in panic, social anxiety, (Ed), Yeon SB (Ed), UpToDate, Waltham, MA obsessive-compulsive, and generalized anxiety (Accessed on July 28, 2015.) Available from: disorders at baseline and in response to relaxation http://www.uptodate.com/contents/treatment-and- and hyperventilation. Int J Psychophysiol. 2013 prognosis-of-diastolic-heart-failure#H5 Jan;87(1):19-27. 6. Kemp AH, Quintana DS, Felmingham KL, Matthews S, Jelinek HF. Depression, comorbid anxiety disorders, and heart rate variability in physically healthy, unmedicated patients: implications for cardiovascular risk. PLoS One. 2012;7(2):e30777. 7. Alpert MA, Mukerji V, Sabeti M, Russell JL, Beitman BD. Mitral valve prolapse, panic disorder, and chest pain. Med Clin North Am. 1991 Sep;75(5):1119-33. 8. Shellock FG. Claustrophobia, anxiety, and emotional distress [Internet] c2015. Playa Del Rey

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