Skip to main content

Panic disorder and incident coronary heart disease: a systematic review and meta-regression in 1 131 612 persons and 58 111 cardiac events

  • P. J. Tully (a1) (a2), D. A. Turnbull (a1), J. Beltrame (a3), J. Horowitz (a3), S. Cosh (a4), H. Baumeister (a2) and G. A. Wittert (a1)...

Substantial healthcare resources are devoted to panic disorder (PD) and coronary heart disease (CHD); however, the association between these conditions remains controversial. Our objective was to conduct a systematic review of studies assessing the association between PD, related syndromes, and incident CHD.


Relevant studies were retrieved from Medline, EMBASE, SCOPUS and PsycINFO without restrictions from inception to January 2015 supplemented with hand-searching. We included studies that reported hazard ratios (HR) or sufficient data to calculate the risk ratio and 95% confidence interval (CI) which were pooled using a random-effects model. Studies utilizing self-reported CHD were ineligible. Twelve studies were included comprising 1 131 612 persons and 58 111 incident CHD cases.


PD was associated with the primary incident CHD endpoint [adjusted HR (aHR) 1.47, 95% CI 1.24–1.74, p < 0.00001] even after excluding angina (aHR 1.49, 95% CI 1.22–1.81, p < 0.00001). High to moderate quality evidence suggested an association with incident major adverse cardiac events (MACE; aHR 1.40, 95% CI 1.16–1.69, p = 0.0004) and myocardial infarction (aHR 1.36, 95% CI 1.12–1.66, p = 0.002). The risk for CHD was significant after excluding depression (aHR 1.64, 95% CI 1.45–1.85) and after depression adjustment (aHR 1.38, 95% CI 1.03–1.87). Age, sex, length of follow-up, socioeconomic status and diabetes were sources of heterogeneity in the primary endpoint.


Meta-analysis showed that PD was independently associated with incident CHD, myocardial infarction and MACE; however, reverse causality cannot be ruled out and there was evidence of heterogeneity.

Corresponding author
* Address for correspondence: Dr P. J. Tully, Discipline of Medicine, The University of Adelaide, South Australia, 5005 Australia. (Email:
Hide All
Albert CM, Chae CU, Rexrode KM, Manson JE, Kawachi I (2005). Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women. Circulation 111, 480487.
Archer J, Bower P, Gilbody S, Lovell K, Richards D, Gask L, Dickens C, Coventry P (2012). Collaborative care for depression and anxiety problems. Cochrane Database of Systematic Reviews 10, CD006525.
Baxter AJ, Vos T, Scott KM, Norman RE, Flaxman AD, Blore J, Whiteford HA (2014). The regional distribution of anxiety disorders: implications for the Global Burden of Disease Study, 2010. International Journal of Methods in Psychiatric Research 23, 422438.
Beitman BD, Mukerji V, Russell JL, Grafting M (1993). Panic disorder in cardiology patients: a review of the Missouri Panic/Cardiology Project. Journal of Psychiatric Research 27 (Suppl. 1), 3546.
Berkman LF, Blumenthal J, Burg M, Carney RM, Catellier D, Cowan MJ, Czajkowski SM, DeBusk R, Hosking J, Jaffe A, Kaufmann PG, Mitchell P, Norman J, Powell LH, Raczynski JM, Schneiderman N (2003). Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. Journal of the American Medical Association 289, 31063116.
Bowen RC, Senthilselvan A, Barale A (2000). Physical illness as an outcome of chronic anxiety disorders. Canadian Journal of Psychiatry 45, 459464.
Bringager CB, Arnesen H, Friis S, Husebye T, Dammen T (2008). A long-term follow-up study of chest pain patients: effect of panic disorder on mortality, morbidity, and quality of life. Cardiology 110, 814.
Carmin CN, Ownby RL, Wiegartz PS, Kondos GT (2008). Women and non-cardiac chest pain: gender differences in symptom presentation. Archives of Women's Mental Health 11, 287293.
Chalmers J, Quintana DS, Abbott MJ, Kemp AH (2014). Anxiety disorders are associated with reduced heart rate variability: a meta-analysis. Frontiers in Psychiatry 5, 80.
Cheng YF, Leu HB, Su CC, Huang CC, Chiang CH, Huang PH, Chung CM, Lin SJ, Chen JW, Chan WL (2013). Association between panic disorder and risk of atrial fibrillation:a nationwide study. Psychosomatic Medicine 75, 3035.
Cicek Y, Durakoglugil ME, Kocaman SA, Guveli H, Cetin M, Erdogan T, Sahin I, Dogan S, Canga A (2012). Increased pulse wave velocity in patients with panic disorder: independent vascular influence of panic disorder on arterial stiffness. Journal of Psychosomatic Research 73, 145148.
Coley KC, Saul MI, Seybert AL (2009). Economic burden of not recognizing panic disorder in the emergency department. Journal of Emergency Medicine 36, 37.
DerSimonian R, Laird N (1986). Meta-analysis in clinical trials. Controlled Clinical Trials 7, 177188.
Duval S, Tweedie R (2000). Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56, 455463.
Edmondson D, Kronish IM, Shaffer JA, Falzon L, Burg MM (2013). Posttraumatic stress disorder and risk for coronary heart disease: a meta-analytic review. American Heart Journal 166, 806814.
Egger M, Davey SG, Schneider M, Minder C (1997). Bias in meta-analysis detected by a simple, graphical test. British Medical Journal 315, 629634.
Feighner JP, Robins E, Guze SB, Woodruff RA Jr., Winokur G, Munoz R (1972). Diagnostic criteria for use in psychiatric research. Archives of General Psychiatry 26, 5763.
Fleet R, Foldes-Busque G, Grégoire J, Harel F, Laurin C, Burelle D, Lavoie K (2014). A study of myocardial perfusion in patients with panic disorder and low risk coronary artery disease after 35% CO2 challenge. Journal of Psychosomatic Research 76, 4145.
Fleet R, Lavoie K, Beitman BD (2000). Is panic disorder associated with coronary artery disease? A critical review of the literature. Journal of Psychosomatic Research 48, 347356.
Fleet R, Lesperance F, Arsenault A, Gregoire J, Lavoie K, Laurin C, Harel F, Burelle D, Lambert J, Beitman B, Frasure-Smith N (2005). Myocardial perfusion study of panic attacks in patients with coronary artery disease. American Journal of Cardiology 96, 10641068.
Fleet RP, Dupuis G, Marchand A, Burelle D, Beitman BD (1997). Detecting panic disorder in emergency department chest pain patients: a validated model to improve recognition. Annals of Behavioral Medicine 19, 124131.
Gan Y, Gong Y, Tong X, Sun H, Cong Y, Dong X, Wang Y, Xu X, Yin X, Deng J, Li L, Cao S, Lu Z (2014). Depression and the risk of coronary heart disease: a meta-analysis of prospective cohort studies. BMC Psychiatry 14, 371.
Glozier N, Tofler GH, Colquhoun DM, Bunker SJ, Clarke DM, Hare DL, Hickie IB, Tatoulis J, Thompson DR, Wilson A, Branagan MG (2013). Psychosocial risk factors for coronary heart disease. Medical Journal of Australia 199, 179180.
Goldberg DP, Krueger RF, Andrews G, Hobbs MJ (2011). Emotional disorders: cluster 4 of the proposed meta-structure for DSM-V and ICD-11. Psychological Medicine 39, 20432059.
Goodwin RD, Davidson KW, Keyes K (2009). Mental disorders and cardiovascular disease among adults in the United States. Journal of Psychosomatic Research 43, 239246.
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ (2008). GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. British Medical Journal 336, 924926.
Hemingway H, Marmot M (1999). Evidence based cardiology: psychosocial factors in the aetiology and prognosis of coronary heart disease. Systematic review of prospective cohort studies. British Medical Journal 318, 14601467.
Higgins JPT, Green S (2008). Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons Ltd: Chichester, West Sussex, UK.
Hoertel N, Le Strat Y, De Maricourt P, Limosin F, Dubertret C (2013). Are subjects in treatment trials of panic disorder representative of patients in routine clinical practice? Results from a national sample. Journal of Affective Disorders 146, 383389.
Huffman JC, Mastromauro CA, Beach SR, Celano CM, Dubois CM, Healy BC, Suarez L, Rollman BL, Januzzi JL (2014). Collaborative care for depression and anxiety disorders in patients with recent cardiac events: the Management of Sadness and Anxiety in Cardiology (MOSAIC) randomized clinical trial. JAMA Internal Medicine 174, 927936.
Isensee B, Wittchen HU, Stein MB, Hofler M, Lieb R (2003). Smoking increases the risk of panic: findings from a prospective community study. Archives of General Psychiatry 60, 692700.
Janszky I, Ahnve S, Lundberg I, Hemmingsson T (2010). Early-onset depression, anxiety, and risk of subsequent coronary heart disease: 37-year follow-up of 49,321 young Swedish men. Journal of the American College Cardiology 56, 3137.
Katerndahl DA (2008). The association between panic disorder and coronary artery disease among primary care patients presenting with chest pain: an updated literature review. Journal of Clinical Psychiatry 10, 276285.
Kawachi I, Colditz GA, Ascherio A, Rimm EB, Giovannucci E, Stampfer MJ, Willett WC (1994). Prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation 89, 19921997.
Kemp AH, Quintana DS, Felmingham KL, Matthews S, Jelinek HF (2012). Depression, comorbid anxiety disorders, and heart rate variability in physically healthy, unmedicated patients: implications for cardiovascular risk. PLoS ONE 7, e30777.
Kuper H, Marmot M, Hemingway H (2002). Systematic review of prospective cohort studies of psychosocial factors in the etiology and prognosis of coronary heart disease. Seminars in Vascular Medicine 2, 267314.
Kuper H, Nicholson A, Kivimaki M, Aitsi-Selmi A, Cavalleri G, Deanfield JE, Heuschmann P, Jouven X, Malyutina S, Mayosi BM, Sans S, Thomsen T, Witteman JCM., Hingorani AD, Lawlor DA, Hemingway H (2009). Evaluating the causal relevance of diverse risk markers: horizontal systematic review. British Medical Journal 339, b4265.
Ladwig KH, Lederbogen F, Albus C, Angermann C, Borggrefe M, Fischer D, Fritzsche K, Haass M, Jordan J, Junger J, Kindermann I, Kollner V, Kuhn B, Scherer M, Seyfarth M, Voller H, Waller C, Herrmann-Lingen C (2014). Position paper on the importance of psychosocial factors in cardiology: update 2013. German Medical Science 12, Doc09.
Lessard MJ, Marchand A, Pelland ME, Belleville G, Vadeboncoeur A, Chauny JM, Poitras J, Dupuis G, Fleet R, Foldes-Busque G, Lavoie KL (2012). Comparing two brief psychological interventions to usual care in panic disorder patients presenting to the emergency department with chest pain. Behavioral and Cognitive Psychotherapy 40, 129147.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009). The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. British Medical Journal 339, b2700.
Loef M, Walach H (2012). The combined effects of healthy lifestyle behaviors on all cause mortality: a systematic review and meta-analysis. Preventive Medicine 55, 163170.
Moylan S, Giorlando F, Nordfjærn T, Berk M (2012). The role of alprazolam for the treatment of panic disorder in Australia. Australia and New Zealand Journal of Psychiatry 46, 212224.
Muotri RW, Bernik MA (2014). Panic disorder and exercise avoidance. Revista Brasileira de Psiquiatria 36, 6875.
Nicholson A, Kuper H, Hemingway H (2006). Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. European Heart Journal 27, 27632774.
Pohl R, Yeragani VK (2001). QT interval variability in panic disorder patients after isoproterenol infusions. International Journal of Neuropsychopharmacology 4, 1720.
Ramadan R, Sheps D, Esteves F, Zafari AM, Bremner JD, Vaccarino V, Quyyumi AA (2013). Myocardial ischemia during mental stress: role of coronary artery disease burden and vasomotion. Journal of the American Heart Association 2, e000321.
Ramos PS, Sardinha A, Nardi AE, Araújo CG (2014). Cardiorespiratory optimal point: a submaximal exercise variable to assess panic disorder patients. PLoS ONE 26, e104932.
Roest AM, Martens EJ, de Jonge P, Denollet J (2010). Anxiety and risk of incident coronary heart disease: a meta-analysis. Journal of the American College of Cardiology 56, 3846.
Rohacek M, Bertolotti A, Grutzmuller N, Simmen U, Marty H, Zimmermann H, Exadaktylos A, Spyridon A (2012). The challenge of triaging chest pain patients: the Bernese university hospital experience. Emergency Medicine International 2012, 975614.
Roy-Byrne P, Craske MG, Sullivan G, Rose RD, Edlund MJ, Lang AJ, Bystritsky A, Welch SS, Chavira DA, Golinelli D, Campbell-Sills L, Sherbourne CD, Stein MB (2010). Delivery of evidence-based treatment for multiple anxiety disorders in primary care: a randomized controlled trial. Journal of the American Medical Association 303, 19211928.
Roy-Byrne PP, Schmidt P, Cannon RO, Diem H, Rubinow DR (1989). Microvascular angina and panic disorder. International Journal of Psychiatry in Medicine 19, 315325.
Rugulies R (2002). Depression as a predictor for coronary heart disease. a review and meta-analysis. American Journal of Preventative Medicine 23, 5161.
Rutledge T, Reis SE, Olson M, Owens J, Kelsey SF, Pepine CJ, Reichek N, Rogers WJ, Merz CN, Sopko G, Cornell CE, Sharaf B, Matthews KA (2001). History of anxiety disorders is associated with a decreased likelihood of angiographic coronary artery disease in women with chest pain: the WISE study. Journal of the American College of Cardiology 37, 780785.
Sardinha A, Nardi AE, Zin WA (2009). Are panic attacks really harmless? The cardiovascular impact of panic disorder. Revista Brasileira de Psiquiatria 31, 5762.
Scherrer JF, Chrusciel T, Zeringue A, Garfield LD, Hauptman PJ, Lustman PJ, Freedland KE, Carney RM, Bucholz KK, Owen R, True WR (2010). Anxiety disorders increase risk for incident myocardial infarction in depressed and nondepressed Veterans Administration patients. American Heart Journal 159, 772779.
Smoller JW, Pollack MH, Wassertheil-Smoller S, Jackson RD, Oberman A, Wong ND, Sheps D (2007). Panic attacks and risk of incident cardiovascular events among postmenopausal women in the Women's Health Initiative Observational Study. Archives of General Psychiatry 64, 11531160.
Stewart JC, Perkins AJ, Callahan CM (2014). Effect of collaborative care for depression on risk of cardiovascular events: data from the IMPACT randomized controlled trial. Psychosomatic Medicine 76, 2937.
Sullivan GM, Kent JM, Kleber M, Martinez JM, Yeragani VK, Gorman JM (2004). Effects of hyperventilation on heart rate and QT variability in panic disorder pre- and post-treatment. Psychiatry Research 125, 2939.
Taylor RE (2001). Death of neurasthenia and its psychological reincarnation: a study of neurasthenia at the National Hospital for the Relief and Cure of the Paralysed and Epileptic, Queen Square, London, 1870–1932. British Journal of Psychiatry 179, 550557.
The GRADE Working Group (2013). GRADE Handbook for Grading Quality of Evidence and Strength of Recommendations. Updated October 2013 (ed. Schünemann H., Brożek J., Guyatt G. and Oxman A. D.).
Tsuchihashi K, Ueshima K, Uchida T, Oh-mura N, Kimura K, Owa M, Yoshiyama M, Miyazaki S, Haze K, Ogawa H, Honda T, Hase M, Kai R, Morii I (2001). Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan. Journal of the American College Cardiology 38, 1118.
Tully PJ (2015). A good time to panic? Premorbid and postmorbid panic disorder in heart failure affects cardiac and psychiatric cause admissions. Australasian Psychiatry 23, 124127.
Tully PJ, Baune BT (2014). Comorbid anxiety disorders alter the association between cardiovascular diseases and depression: the German National Health Interview and Examination Survey. Social Psychiatry and Psychiatric Epidemiology 49, 683691.
Tully PJ, Cosh SM, Baumeister H (2014). The anxious heart in whose mind? A systematic review and meta-regression of factors associated with anxiety disorder diagnosis, treatment and morbidity risk in coronary heart disease. Journal of Psychosomatic Research 77, 439448.
Tully PJ, Wittert GA, Turnbull DA, Beltrame JF, Horowitz JD, Cosh S, Baumeister H (2015). Panic disorder and incident coronary heart disease: a systematic review and meta-analysis protocol. Systematic Reviews 4, 33.
Van Apeldoorn FJ, Van Hout WJ, Timmerman ME, Mersch PP, den Boer JA (2013). Rate of improvement during and across three treatments for panic disorder with or without agoraphobia: cognitive behavioral therapy, selective serotonin reuptake inhibitor or both combined. Journal of Affective Disorders 150, 313319.
Viswanathan M, Berkman ND (2012). Development of the RTI item bank on risk of bias and precision of observational studies. Journal of Clinical Epidemiology 65, 163178.
Vural M, Satiroglu O, Akbas B, Goksel I, Karabay O (2009). Coronary artery disease in association with depression or anxiety among patients undergoing angiography to investigate chest pain. Texas Heart Institute Journal 36, 1723.
Walsh JJ (1912). Cardiac neuroses. In Psychotherapy: Including the History of the Use of Mental Influence, Directly and Indirectly in Healing and the Principles for the Application of Energies Derived from the Mind to the Treatment of Disease, pp. 321328. D Appleton & Company: New York, NY, USA.
Walters K, Rait G, Petersen I, Williams R, Nazareth I (2008). Panic disorder and risk of new onset coronary heart disease, acute myocardial infarction, and cardiac mortality: cohort study using the general practice research database. European Heart Journal 29, 29812988.
Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jonsson B, Olesen J, Allgulander C, Alonso J, Faravelli C, Fratiglioni L, Jennum P, Lieb R, Maercker A, van Os J, Preisig M, Salvador-Carulla L, Simon R, Steinhausen HC (2011). The size and burden of mental disorders and other disorders of the brain in Europe 2010. European Neuropsychopharmacology 21, 655679.
Wulsin LR, Singal BM (2003). Do depressive symptoms increase the risk for the onset of coronary disease? A systematic quantitative review. Psychosomatic Medicine 65, 201210.
Yeragani VK, Pohl R, Balon R, Jampala VC, Jayaraman A (2002). Twenty-four-hour QT interval variability: increased QT variability during sleep in patients with panic disorder. Neuropsychobiology 46, 16.
Yeragani VK, Pohl R, Bar KJ, Chokka P, Tancer M (2007). Exaggerated beat-to-beat R amplitude variability in patients with panic disorder after intravenous isoproterenol. Neuropsychobiology 55, 213218.
Yeragani VK, Pohl R, Berger R, Balon R, Ramesh C, Glitz D, Srinivasan K, Weinberg P (1993). Decreased heart rate variability in panic disorder patients: a study of power-spectral analysis of heart rate. Psychiatry Research 46, 89103.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary Materials

Tully supplementary material
Tables S1-S6 and Figure S1

 Word (64 KB)
64 KB


Altmetric attention score

Full text views

Total number of HTML views: 7
Total number of PDF views: 121 *
Loading metrics...

Abstract views

Total abstract views: 664 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 24th November 2017. This data will be updated every 24 hours.