Novel Insights from Clinical Experience Cardiology 2015;130:106–111 DOI: 10.1159/000369296
Received: October 23, 2014 Accepted: October 23, 2014 Published online: January 20, 2015
Bronchogenic Stress Cardiomyopathy: A Case Series Adil Rajwani Zulfiquar Adam James Anthony Hall Division of Cardiology and Cardiothoracic Surgery, The James Cook University Hospital, Middlesbrough, UK
Established Facts • Acute exacerbation of chronic obstructive pulmonary disease (COPD) is a proportionately common but under-appreciated precipitant of stress (takotsubo) cardiomyopathy. • The symptomatic presentation of stress cardiomyopathy is heterogeneous; no clear rationale for this currently exists.
Novel Insights
Key Words Stress (takotsubo) cardiomyopathy · Chronic obstructive pulmonary disease · Beta-agonist · Salbutamol
Abstract Despite a growing awareness of stress (takotsubo) cardiomyopathy, the diversity in precipitants beyond emotional distress remains under-appreciated. Emerging data impli-
© 2015 S. Karger AG, Basel 0008–6312/15/1302–0106$39.50/0 E-Mail [email protected] www.karger.com/crd
cate a differential influence of precipitant type on the variable presentations of stress cardiomyopathy. We outline 5 cases of stress cardiomyopathy where the precipitant was an acute exacerbation of chronic obstructive pulmonary disease treated with high-dose bronchodilator therapy. In this setting, an atypical and insidious presentation of the stress cardiomyopathy was consistently observed that was difficult to distinguish from the acute airway exacerbation itself, with an absence of chest pain in particular. Scrutiny of published
Dr. A. Rajwani Division of Cardiology and Cardiothoracic Surgery The James Cook University Hospital, Marton Road Middlesbrough TS4 3BW (UK) E-Mail adilrajwani @ hotmail.com
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/7/2015 9:18:50 AM
• A bronchogenic subgroup of stress cardiomyopathy is observed in the setting of acute exacerbation of COPD, with an insidious presentation predominated by dyspnoea and an absence of chest pain that is difficult to distinguish from the precipitating episode of bronchospasm. • High-dose β-agonist therapy may be implicated in this association. • The key role of repeat ECG acquisition as a simple bedside investigation when the course of an acute exacerbation of COPD is protracted or progressive is highlighted.
Introduction
Stress (takotsubo) cardiomyopathy is now a widely recognized syndrome, characterized by a transient left ventricular systolic dysfunction that most frequently manifests as an apical ballooning. Early reports suggested a highly typical presentation precipitated by intense emotional upset, with symptoms masquerading as an acute coronary syndrome [1, 2]. However, recent registry data have demonstrated significant diversity in both precipitants and presenting symptoms [3, 4]. No clear rationale for this heterogeneity currently exists, nor have the underlying biological mechanisms been fully elucidated. We outline an atypical yet strikingly uniform clinical presentation in 5 consecutive cases in which the precipitant was an acute exacerbation of chronic airway disease, highlighting the existence of a novel bronchogenic subgroup of stress cardiomyopathy.
Case Series Description
Patient Characteristics Five consecutive patients were referred to our unit over a 1-year period with a final diagnosis of stress cardiomyopathy precipitated by acute exacerbation of chronic obstructive airway disease (COPD). All patients were post-menopausal Caucasian females, with a mean age of 70 years (table 1). All cases fulfilled the criteria of the American Thoracic Society/European Respiratory Society clinical practice guidelines for a pre-existing diagnosis of COPD with prior baseline spirometric evidence of airway limitation [5]. Two patients were active smokers, 2 had desisted completely and 1 had never used tobacco. None had any history of symptomatic coronary artery disease. In 1 patient, the admission was for recurrence of a very similar presentation of stress cardiomyopathy 3 years previously, again in the setting of acute exacerbation of COPD. Bronchogenic Stress Cardiomyopathy
Presentation All patients presented via the emergency department with increased dyspnoea and expectoration of sufficient severity to justify admission to the medical assessment unit. Two patients had consulted with primary care in the preceding 24–48 h for the same symptoms, but had not been considered as requiring admission at that point. One patient also reported unwitnessed syncope, but none reported constricting chest pain. All cases exhibited wheeze with a prolonged expiratory phase at initial presentation. None had clinical or radiological evidence of pulmonary oedema. None reported any history of recent emotional distress, intracranial bleeding or phaeochromocytoma. All received a diagnosis of acute exacerbation of COPD at assessment by a consultant physician. Re-evaluation over the course of 1–3 days was prompted by an apparent deterioration or persistence of respiratory distress, and new ECG abnormalities at this point led to urgent cardiology review in 4 of the cases and an emergency referral for consideration of primary angioplasty in the 5th case. Pharmacotherapy All patients were receiving long-term inhaled-steroid therapy and inhaled short-acting β-agonists when required. Three of the cases were also on co-administered inhaled long-acting β-agonists, and 2 on long-acting muscarinic receptor antagonists. Two patients had access to nebulized salbutamol at home, 1 used long-term oxygen therapy and 1 received daily oral aminophylline. Acute exacerbations were treated in all cases with an oral steroid and nebulized salbutamol (2.5 mg in 4 cases and an increase in the regular dose to 5 mg in 1 case). All patients also reported an increased use of inhaled β-agonist prior to admission in response to the advent of wheeze. Nebulized muscarinic antagonists were also used in 3 presentations. Investigations At the time of review by a cardiologist, all cases exhibited new abnormalities on ECG. In particular, pathological T-wave inversion, ST elevation without reciprocal ST depression and prolonged corrected QT (QTc) interval were typical (fig. 1a–c). Pathological Q-waves were also present in 3 cases. By contrast, upon admission, these ECG abnormalities had typically been minimal or absent. Apical and mid or isolated apical hypokinesis was present on echocardiography in all cases with a ballooning appearance typical of stress cardiomyopathy. None was found to have basal or isolated mid-ventricular hypokinesis. Inpatient coronary angiography excluded obstrucCardiology 2015;130:106–111 DOI: 10.1159/000369296
107
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/7/2015 9:18:50 AM
single-case reports reveals a similar atypical presentation; this supports the existence of a novel bronchogenic subgroup of stress cardiomyopathy. A key role of repeat ECG evaluation in distinguishing protracted but uncomplicated bronchospasm from bronchogenic stress cardiomyopathy is highlighted. Further data are now required to examine whether high-dose β-agonist therapy is implicated in this association. © 2015 S. Karger AG, Basel
Table 1. Summary of patient characteristics across 5 presentations
Presentation ID Demographics Age, years Gender, M/F Smoking history Admission Admitting complaint Accepting department Chest pain Dyspnoea Wheeze Pulse Blood pressure Temperature, °C Usual medication Salbutamol (inhaled) Salbutamol (nebulized) Steroid (inhaled) LABA (inhaled) Tiotropium (inhaled) LTOT Montelukast Theophylline (oral) Acute medication Salbutamol (nebulized) Atrovent (nebulized) Steroid oral/i.v. Antibiotic Aminophylline i.v. Investigations Neutrophils, ×109/l CRP, mg/l Peak troponin I, ng/ml ECG rhythm ST elevation T-wave inversion QTc (ms) Q-waves Coronary angiography Left ventricular RWMA
1
2
3a
4
5
80 F ex-smoker
55 F current
65 F ex-smoker
77 F never
71 F current
syncope MAU no yes yes 77 125/64 37.0
dyspnoea MAU no yes yes 113 117/90 36.5
dyspnoea MAU no yes yes 131 110/41 36.0
dyspnoea MAU no yes yes 109 107/89 35.9
dyspnoea MAU no yes yes 104 125/71 36.0
yes – yes – – – – –
yes yes yes yes yes – – –
yes yes yes yes yes yes – –
yes – yes yes – – – yes
yes – yes – – – – –
yes – yes yes –
yes – yes – –
yes yes yes – –
yes yes yes yes –
yes yes yes yes –
7.9 17 5.46 sinus yes yes 500 yes no/minor CAD apical
10.2 26 2.43 sinus yes yes 519 no no/minor CAD apical, mid
13.0 21 3.84 sinus minimal yes 507 yes – apical, mid
20.7 98 4.18 sinus yes yes 633 no no/minor CAD apical, mid
4.2 23 4.13 sinus yes no 442 yes no/minor CAD apical, mid
CAD = Coronary artery disease; CCU = coronary care unit; CRP = C-reactive protein; i.v. = intravenous; LABA = long-acting β-agonist; LTOT = long-term oxygen therapy; MAU = medical assessment unit; RWMA = regional wall motion abnormalities. a Recurrent presentation of stress cardiomyopathy.
108
Cardiology 2015;130:106–111 DOI: 10.1159/000369296
Discussion
In this case series, we outline our experience of 5 patients with stress cardiomyopathy in the setting of acute exacerbation of COPD. To the best of our knowledge, this is the first series specifically examining the underappreciated interaction of these two pathologies. The Rajwani/Adam/Hall
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/7/2015 9:18:50 AM
tive culprit coronary stenosis in 4 cases, but was not undertaken in the other case due to this representing a recurrence of stress cardiomyopathy and following a rapid resolution of hypokinesis. Ventricular function had normalized in all patients at 3-month follow-up. One year later, all the patients remain free of cardiovascular symptoms.
Color version available online
a
b
c
Bronchogenic Stress Cardiomyopathy
Cardiology 2015;130:106–111 DOI: 10.1159/000369296
109
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/7/2015 9:18:50 AM
Fig. 1. a–c Sample ECGs from 3 patients with bronchogenic stress cardiomyopathy, acquired due to protracted or progressive respiratory distress. Key features were deep T-wave inversion, QTc interval prolongation and ST-segment elevation without reciprocal ST-segment depression.
110
Cardiology 2015;130:106–111 DOI: 10.1159/000369296
dose epinephrine, effected via a switch in ligand-mediated trafficking of the β2-adrenergic receptors from stimulatory G-protein to inhibitory G-protein subcellular signalling pathways [14]. Catecholamine levels are likely to be elevated during acute respiratory distress, which alone may account for the incidence of stress cardiomyopathy in this setting. However, an interaction of myocyte function with high-dose β-agonist therapy has also been demonstrated. In rodents, myocyte injury results from calcium leakage from ryanodine receptors in response to high-dose isoproterenol, a non-selective β-adrenoreceptor agonist historically used in the treatment of asthma [15]. Subcutaneous administration of high-dose salbutamol in rats induced myocardial oedema and inflammatory changes, an observation not found with low-dose administration [16]. Conformational changes of β2-adrenergic receptors in response to these partial agonists might alter the degree or rate at which an inhibitory subcellular signalling pathway is initiated, potentially influencing the phenotype of any subsequent stress cardiomyopathy. This is clinically relevant in a setting where β-agonist therapy is otherwise the standard of care. In our series, only 2 patients were active smokers around the time of presentation, suggesting that it was unlikely that nicotine was directly implicated.
Conclusions
This series supports a greater appreciation of the role of acute COPD exacerbation as a precipitant of stress cardiomyopathy and, in particular, highlights the existence of a novel bronchogenic subgroup. This association also complements emerging evidence for an interaction between precipitant type and the specific symptoms exhibited, providing insight into the otherwise unexplained heterogeneous presentation of stress cardiomyopathy. Further data are required to clarify whether high-dose bronchodilator therapy is implicated in this interaction. Given the overlapping symptomatology of bronchospasm versus bronchogenic stress cardiomyopathy, the importance of ECG evaluation is underscored where the clinical course of an acute exacerbation of chronic airway disease appears atypical.
Conflict of Interest All authors declare no conflicts of interest.
Rajwani/Adam/Hall
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/7/2015 9:18:50 AM
clinical course of these patients is intriguing, with a presentation that is distinct from that typically reported in stress cardiomyopathy. In particular, we observed an insidious symptomatology with respect to the cardiomyopathy, with a notable absence of chest pain in all cases and emergency referral due to an emergency for presumed ST-elevation myocardial infarction in only 1 case. Rather, the presentations were predominantly a progressive or relapsing dyspnoea initially attributed (by the referring clinician) to a suboptimal response to standard treatment for bronchospasm. This contrasts with a presentation predominated by chest pain in the majority of patients with stress cardiomyopathy in a systematic review of 14 studies [6]. While the occurrence of stress cardiomyopathy during chronic respiratory disease exacerbation has not been systematically reviewed, isolated case reports have evaluated this interaction [7–11]. Scrutiny of these also reveals an insidious presentation predominated by a ‘double dyspnoea’ rather than chest pain, which made it difficult to distinguish from the preceding or accompanying acute respiratory illness. In parallel, other authors have noted an influence of the precipitant type on presentation, for example, when comparing physical and emotional triggers [12]. Accruing data thus point towards a distinct bronchogenic subgroup. Patient characteristics in our series were otherwise typical, with a preponderance of post-menopausal women, apical hypokinesis (online suppl. video 1; for all online suppl. material, see www.karger.com/doi/10.1159/000369296) and a favourable overall prognosis despite significant inpatient morbidity. Given the significant symptomatic overlap of bronchogenic stress cardiomyopathy and COPD exacerbation itself, it is likely that this subgroup frequently remains undetected. In our series, ECG abnormalities were universally exhibited during the evolution of cardiomyopathy, e.g. profound T-wave inversion, widespread ST-segment elevation and prolongation of the QTc interval. In fact, new abnormalities appearing on ECG were crucial in all cases in arousing suspicion of acute cardiomyopathy, which highlights the value of this simple bedside investigation when the response of COPD exacerbation to treatment is suboptimal or atypical. The mechanisms underlying stress cardiomyopathy remain incompletely understood. An adverse response to an exaggerated catecholamine milieu appears most likely [13], mediated by differential influences on myocardial β-adrenergic receptors. Experimental data highlight a paradoxical negative inotropic response to high-
References
Bronchogenic Stress Cardiomyopathy
7 Bilan A, Ignatowicz A, Mosiewicz J, Wysokinski A: Dyspnea as a dominant clinical manifestation in a patient with takotsubo cardiomyopathy treated for chronic obstructive pulmonary disease and hyperthyroidism. Polsk Arch Med Wewnetrznej 2009;119:265–268. 8 Mendoza I, Novaro GM: Repeat recurrence of takotsubo cardiomyopathy related to inhaled beta-2-adrenoceptor agonists. World J Cardiol 2012;4:211–213. 9 Khouri S, Imran N: Stress cardiomyopathy (takotsubo cardiomyopathy). Clin Med Cardiol 2009;3:93–99. 10 Salahuddin FF, Sloane P, Buescher P, Agarunov L, Sreeramoju D: A case of apical ballooning syndrome in a male with status asthmaticus, highlighting the role of B2 agonists in the pathophysiology of a reversible cardiomyopathy. J Community Hosp Intern Med Perspect 2013, DOI: 10.3402/jchimp.v3i2.20530. 11 Pham J, Bruhl S, Sheikh M: COPD exacerbation with concurrent stress cardiomyopathy: a case of double dyspnoea. BJMP 2011;4:a407.
12 Song BG, Yang HS, Hwang HK, Kang GH, Park YH, Chun WJ, Oh JH: The impact of stressor patterns on clinical features in patients with tako-tsubo cardiomyopathy: experiences of two tertiary cardiovascular centers. Clin Cardiol 2012;35:E6–E13. 13 Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, Wu KC, Rade JJ, Bivalacqua TJ, Champion HC: Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352:539–548. 14 Paur H, Wright PT, Sikkel MB, Tranter MH, Mansfield C, O’Gara P, Stuckey DJ, Nikolaev VO, Diakonov I, Pannell L, et al: High levels of circulating epinephrine trigger apical cardiodepression in a beta2-adrenergic receptor/ Gi-dependent manner: a new model of takotsubo cardiomyopathy. Circulation 2012; 126: 697–706. 15 Ellison GM, Torella D, Karakikes I, Purushothaman S, Curcio A, Gasparri C, Indolfi C, Cable NT, Goldspink DF, Nadal-Ginard B: Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells. J Biol Chem 2007;282:11397–11409. 16 Magnusson G, Hansson E: Myocardial necrosis in the rat: a comparison between isoprenaline, orciprenaline, salbutamol and terbutaline. Cardiology 1973;58:174–180.
Cardiology 2015;130:106–111 DOI: 10.1159/000369296
111
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/7/2015 9:18:50 AM
1 Dote K, Sato H, Tateishi H, Uchida T, Ishihara M: Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases. J Cardiol 1991;21:203–214. 2 Pavin D, Le Breton H, Daubert C: Human stress cardiomyopathy mimicking acute myocardial syndrome. Heart 1997; 78: 509– 511. 3 Sharkey SW, Windenburg DC, Lesser JR, Maron MS, Hauser RG, Lesser JN, Haas TS, Hodges JS, Maron BJ: Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol 2010; 55: 333–341. 4 Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, Carbone I, Muellerleile K, Aldrovandi A, Francone M, Desch S, Gutberlet M, Strohm O, et al: Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA 2011;306:277–286. 5 Celli BR, MacNee W, Force AET: Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004; 23: 932– 946. 6 Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E: Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J 2006; 27: 1523– 1529.
Received: October 23, 2014 Accepted: October 23, 2014 Published online: January 20, 2015
Bronchogenic Stress Cardiomyopathy: A Case Series Adil Rajwani Zulfiquar Adam James Anthony Hall Division of Cardiology and Cardiothoracic Surgery, The James Cook University Hospital, Middlesbrough, UK
Established Facts • Acute exacerbation of chronic obstructive pulmonary disease (COPD) is a proportionately common but under-appreciated precipitant of stress (takotsubo) cardiomyopathy. • The symptomatic presentation of stress cardiomyopathy is heterogeneous; no clear rationale for this currently exists.
Novel Insights
Key Words Stress (takotsubo) cardiomyopathy · Chronic obstructive pulmonary disease · Beta-agonist · Salbutamol
Abstract Despite a growing awareness of stress (takotsubo) cardiomyopathy, the diversity in precipitants beyond emotional distress remains under-appreciated. Emerging data impli-
© 2015 S. Karger AG, Basel 0008–6312/15/1302–0106$39.50/0 E-Mail [email protected] www.karger.com/crd
cate a differential influence of precipitant type on the variable presentations of stress cardiomyopathy. We outline 5 cases of stress cardiomyopathy where the precipitant was an acute exacerbation of chronic obstructive pulmonary disease treated with high-dose bronchodilator therapy. In this setting, an atypical and insidious presentation of the stress cardiomyopathy was consistently observed that was difficult to distinguish from the acute airway exacerbation itself, with an absence of chest pain in particular. Scrutiny of published
Dr. A. Rajwani Division of Cardiology and Cardiothoracic Surgery The James Cook University Hospital, Marton Road Middlesbrough TS4 3BW (UK) E-Mail adilrajwani @ hotmail.com
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/7/2015 9:18:50 AM
• A bronchogenic subgroup of stress cardiomyopathy is observed in the setting of acute exacerbation of COPD, with an insidious presentation predominated by dyspnoea and an absence of chest pain that is difficult to distinguish from the precipitating episode of bronchospasm. • High-dose β-agonist therapy may be implicated in this association. • The key role of repeat ECG acquisition as a simple bedside investigation when the course of an acute exacerbation of COPD is protracted or progressive is highlighted.
Introduction
Stress (takotsubo) cardiomyopathy is now a widely recognized syndrome, characterized by a transient left ventricular systolic dysfunction that most frequently manifests as an apical ballooning. Early reports suggested a highly typical presentation precipitated by intense emotional upset, with symptoms masquerading as an acute coronary syndrome [1, 2]. However, recent registry data have demonstrated significant diversity in both precipitants and presenting symptoms [3, 4]. No clear rationale for this heterogeneity currently exists, nor have the underlying biological mechanisms been fully elucidated. We outline an atypical yet strikingly uniform clinical presentation in 5 consecutive cases in which the precipitant was an acute exacerbation of chronic airway disease, highlighting the existence of a novel bronchogenic subgroup of stress cardiomyopathy.
Case Series Description
Patient Characteristics Five consecutive patients were referred to our unit over a 1-year period with a final diagnosis of stress cardiomyopathy precipitated by acute exacerbation of chronic obstructive airway disease (COPD). All patients were post-menopausal Caucasian females, with a mean age of 70 years (table 1). All cases fulfilled the criteria of the American Thoracic Society/European Respiratory Society clinical practice guidelines for a pre-existing diagnosis of COPD with prior baseline spirometric evidence of airway limitation [5]. Two patients were active smokers, 2 had desisted completely and 1 had never used tobacco. None had any history of symptomatic coronary artery disease. In 1 patient, the admission was for recurrence of a very similar presentation of stress cardiomyopathy 3 years previously, again in the setting of acute exacerbation of COPD. Bronchogenic Stress Cardiomyopathy
Presentation All patients presented via the emergency department with increased dyspnoea and expectoration of sufficient severity to justify admission to the medical assessment unit. Two patients had consulted with primary care in the preceding 24–48 h for the same symptoms, but had not been considered as requiring admission at that point. One patient also reported unwitnessed syncope, but none reported constricting chest pain. All cases exhibited wheeze with a prolonged expiratory phase at initial presentation. None had clinical or radiological evidence of pulmonary oedema. None reported any history of recent emotional distress, intracranial bleeding or phaeochromocytoma. All received a diagnosis of acute exacerbation of COPD at assessment by a consultant physician. Re-evaluation over the course of 1–3 days was prompted by an apparent deterioration or persistence of respiratory distress, and new ECG abnormalities at this point led to urgent cardiology review in 4 of the cases and an emergency referral for consideration of primary angioplasty in the 5th case. Pharmacotherapy All patients were receiving long-term inhaled-steroid therapy and inhaled short-acting β-agonists when required. Three of the cases were also on co-administered inhaled long-acting β-agonists, and 2 on long-acting muscarinic receptor antagonists. Two patients had access to nebulized salbutamol at home, 1 used long-term oxygen therapy and 1 received daily oral aminophylline. Acute exacerbations were treated in all cases with an oral steroid and nebulized salbutamol (2.5 mg in 4 cases and an increase in the regular dose to 5 mg in 1 case). All patients also reported an increased use of inhaled β-agonist prior to admission in response to the advent of wheeze. Nebulized muscarinic antagonists were also used in 3 presentations. Investigations At the time of review by a cardiologist, all cases exhibited new abnormalities on ECG. In particular, pathological T-wave inversion, ST elevation without reciprocal ST depression and prolonged corrected QT (QTc) interval were typical (fig. 1a–c). Pathological Q-waves were also present in 3 cases. By contrast, upon admission, these ECG abnormalities had typically been minimal or absent. Apical and mid or isolated apical hypokinesis was present on echocardiography in all cases with a ballooning appearance typical of stress cardiomyopathy. None was found to have basal or isolated mid-ventricular hypokinesis. Inpatient coronary angiography excluded obstrucCardiology 2015;130:106–111 DOI: 10.1159/000369296
107
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/7/2015 9:18:50 AM
single-case reports reveals a similar atypical presentation; this supports the existence of a novel bronchogenic subgroup of stress cardiomyopathy. A key role of repeat ECG evaluation in distinguishing protracted but uncomplicated bronchospasm from bronchogenic stress cardiomyopathy is highlighted. Further data are now required to examine whether high-dose β-agonist therapy is implicated in this association. © 2015 S. Karger AG, Basel
Table 1. Summary of patient characteristics across 5 presentations
Presentation ID Demographics Age, years Gender, M/F Smoking history Admission Admitting complaint Accepting department Chest pain Dyspnoea Wheeze Pulse Blood pressure Temperature, °C Usual medication Salbutamol (inhaled) Salbutamol (nebulized) Steroid (inhaled) LABA (inhaled) Tiotropium (inhaled) LTOT Montelukast Theophylline (oral) Acute medication Salbutamol (nebulized) Atrovent (nebulized) Steroid oral/i.v. Antibiotic Aminophylline i.v. Investigations Neutrophils, ×109/l CRP, mg/l Peak troponin I, ng/ml ECG rhythm ST elevation T-wave inversion QTc (ms) Q-waves Coronary angiography Left ventricular RWMA
1
2
3a
4
5
80 F ex-smoker
55 F current
65 F ex-smoker
77 F never
71 F current
syncope MAU no yes yes 77 125/64 37.0
dyspnoea MAU no yes yes 113 117/90 36.5
dyspnoea MAU no yes yes 131 110/41 36.0
dyspnoea MAU no yes yes 109 107/89 35.9
dyspnoea MAU no yes yes 104 125/71 36.0
yes – yes – – – – –
yes yes yes yes yes – – –
yes yes yes yes yes yes – –
yes – yes yes – – – yes
yes – yes – – – – –
yes – yes yes –
yes – yes – –
yes yes yes – –
yes yes yes yes –
yes yes yes yes –
7.9 17 5.46 sinus yes yes 500 yes no/minor CAD apical
10.2 26 2.43 sinus yes yes 519 no no/minor CAD apical, mid
13.0 21 3.84 sinus minimal yes 507 yes – apical, mid
20.7 98 4.18 sinus yes yes 633 no no/minor CAD apical, mid
4.2 23 4.13 sinus yes no 442 yes no/minor CAD apical, mid
CAD = Coronary artery disease; CCU = coronary care unit; CRP = C-reactive protein; i.v. = intravenous; LABA = long-acting β-agonist; LTOT = long-term oxygen therapy; MAU = medical assessment unit; RWMA = regional wall motion abnormalities. a Recurrent presentation of stress cardiomyopathy.
108
Cardiology 2015;130:106–111 DOI: 10.1159/000369296
Discussion
In this case series, we outline our experience of 5 patients with stress cardiomyopathy in the setting of acute exacerbation of COPD. To the best of our knowledge, this is the first series specifically examining the underappreciated interaction of these two pathologies. The Rajwani/Adam/Hall
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/7/2015 9:18:50 AM
tive culprit coronary stenosis in 4 cases, but was not undertaken in the other case due to this representing a recurrence of stress cardiomyopathy and following a rapid resolution of hypokinesis. Ventricular function had normalized in all patients at 3-month follow-up. One year later, all the patients remain free of cardiovascular symptoms.
Color version available online
a
b
c
Bronchogenic Stress Cardiomyopathy
Cardiology 2015;130:106–111 DOI: 10.1159/000369296
109
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/7/2015 9:18:50 AM
Fig. 1. a–c Sample ECGs from 3 patients with bronchogenic stress cardiomyopathy, acquired due to protracted or progressive respiratory distress. Key features were deep T-wave inversion, QTc interval prolongation and ST-segment elevation without reciprocal ST-segment depression.
110
Cardiology 2015;130:106–111 DOI: 10.1159/000369296
dose epinephrine, effected via a switch in ligand-mediated trafficking of the β2-adrenergic receptors from stimulatory G-protein to inhibitory G-protein subcellular signalling pathways [14]. Catecholamine levels are likely to be elevated during acute respiratory distress, which alone may account for the incidence of stress cardiomyopathy in this setting. However, an interaction of myocyte function with high-dose β-agonist therapy has also been demonstrated. In rodents, myocyte injury results from calcium leakage from ryanodine receptors in response to high-dose isoproterenol, a non-selective β-adrenoreceptor agonist historically used in the treatment of asthma [15]. Subcutaneous administration of high-dose salbutamol in rats induced myocardial oedema and inflammatory changes, an observation not found with low-dose administration [16]. Conformational changes of β2-adrenergic receptors in response to these partial agonists might alter the degree or rate at which an inhibitory subcellular signalling pathway is initiated, potentially influencing the phenotype of any subsequent stress cardiomyopathy. This is clinically relevant in a setting where β-agonist therapy is otherwise the standard of care. In our series, only 2 patients were active smokers around the time of presentation, suggesting that it was unlikely that nicotine was directly implicated.
Conclusions
This series supports a greater appreciation of the role of acute COPD exacerbation as a precipitant of stress cardiomyopathy and, in particular, highlights the existence of a novel bronchogenic subgroup. This association also complements emerging evidence for an interaction between precipitant type and the specific symptoms exhibited, providing insight into the otherwise unexplained heterogeneous presentation of stress cardiomyopathy. Further data are required to clarify whether high-dose bronchodilator therapy is implicated in this interaction. Given the overlapping symptomatology of bronchospasm versus bronchogenic stress cardiomyopathy, the importance of ECG evaluation is underscored where the clinical course of an acute exacerbation of chronic airway disease appears atypical.
Conflict of Interest All authors declare no conflicts of interest.
Rajwani/Adam/Hall
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/7/2015 9:18:50 AM
clinical course of these patients is intriguing, with a presentation that is distinct from that typically reported in stress cardiomyopathy. In particular, we observed an insidious symptomatology with respect to the cardiomyopathy, with a notable absence of chest pain in all cases and emergency referral due to an emergency for presumed ST-elevation myocardial infarction in only 1 case. Rather, the presentations were predominantly a progressive or relapsing dyspnoea initially attributed (by the referring clinician) to a suboptimal response to standard treatment for bronchospasm. This contrasts with a presentation predominated by chest pain in the majority of patients with stress cardiomyopathy in a systematic review of 14 studies [6]. While the occurrence of stress cardiomyopathy during chronic respiratory disease exacerbation has not been systematically reviewed, isolated case reports have evaluated this interaction [7–11]. Scrutiny of these also reveals an insidious presentation predominated by a ‘double dyspnoea’ rather than chest pain, which made it difficult to distinguish from the preceding or accompanying acute respiratory illness. In parallel, other authors have noted an influence of the precipitant type on presentation, for example, when comparing physical and emotional triggers [12]. Accruing data thus point towards a distinct bronchogenic subgroup. Patient characteristics in our series were otherwise typical, with a preponderance of post-menopausal women, apical hypokinesis (online suppl. video 1; for all online suppl. material, see www.karger.com/doi/10.1159/000369296) and a favourable overall prognosis despite significant inpatient morbidity. Given the significant symptomatic overlap of bronchogenic stress cardiomyopathy and COPD exacerbation itself, it is likely that this subgroup frequently remains undetected. In our series, ECG abnormalities were universally exhibited during the evolution of cardiomyopathy, e.g. profound T-wave inversion, widespread ST-segment elevation and prolongation of the QTc interval. In fact, new abnormalities appearing on ECG were crucial in all cases in arousing suspicion of acute cardiomyopathy, which highlights the value of this simple bedside investigation when the response of COPD exacerbation to treatment is suboptimal or atypical. The mechanisms underlying stress cardiomyopathy remain incompletely understood. An adverse response to an exaggerated catecholamine milieu appears most likely [13], mediated by differential influences on myocardial β-adrenergic receptors. Experimental data highlight a paradoxical negative inotropic response to high-
References
Bronchogenic Stress Cardiomyopathy
7 Bilan A, Ignatowicz A, Mosiewicz J, Wysokinski A: Dyspnea as a dominant clinical manifestation in a patient with takotsubo cardiomyopathy treated for chronic obstructive pulmonary disease and hyperthyroidism. Polsk Arch Med Wewnetrznej 2009;119:265–268. 8 Mendoza I, Novaro GM: Repeat recurrence of takotsubo cardiomyopathy related to inhaled beta-2-adrenoceptor agonists. World J Cardiol 2012;4:211–213. 9 Khouri S, Imran N: Stress cardiomyopathy (takotsubo cardiomyopathy). Clin Med Cardiol 2009;3:93–99. 10 Salahuddin FF, Sloane P, Buescher P, Agarunov L, Sreeramoju D: A case of apical ballooning syndrome in a male with status asthmaticus, highlighting the role of B2 agonists in the pathophysiology of a reversible cardiomyopathy. J Community Hosp Intern Med Perspect 2013, DOI: 10.3402/jchimp.v3i2.20530. 11 Pham J, Bruhl S, Sheikh M: COPD exacerbation with concurrent stress cardiomyopathy: a case of double dyspnoea. BJMP 2011;4:a407.
12 Song BG, Yang HS, Hwang HK, Kang GH, Park YH, Chun WJ, Oh JH: The impact of stressor patterns on clinical features in patients with tako-tsubo cardiomyopathy: experiences of two tertiary cardiovascular centers. Clin Cardiol 2012;35:E6–E13. 13 Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, Wu KC, Rade JJ, Bivalacqua TJ, Champion HC: Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352:539–548. 14 Paur H, Wright PT, Sikkel MB, Tranter MH, Mansfield C, O’Gara P, Stuckey DJ, Nikolaev VO, Diakonov I, Pannell L, et al: High levels of circulating epinephrine trigger apical cardiodepression in a beta2-adrenergic receptor/ Gi-dependent manner: a new model of takotsubo cardiomyopathy. Circulation 2012; 126: 697–706. 15 Ellison GM, Torella D, Karakikes I, Purushothaman S, Curcio A, Gasparri C, Indolfi C, Cable NT, Goldspink DF, Nadal-Ginard B: Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells. J Biol Chem 2007;282:11397–11409. 16 Magnusson G, Hansson E: Myocardial necrosis in the rat: a comparison between isoprenaline, orciprenaline, salbutamol and terbutaline. Cardiology 1973;58:174–180.
Cardiology 2015;130:106–111 DOI: 10.1159/000369296
111
Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/7/2015 9:18:50 AM
1 Dote K, Sato H, Tateishi H, Uchida T, Ishihara M: Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases. J Cardiol 1991;21:203–214. 2 Pavin D, Le Breton H, Daubert C: Human stress cardiomyopathy mimicking acute myocardial syndrome. Heart 1997; 78: 509– 511. 3 Sharkey SW, Windenburg DC, Lesser JR, Maron MS, Hauser RG, Lesser JN, Haas TS, Hodges JS, Maron BJ: Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol 2010; 55: 333–341. 4 Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, Carbone I, Muellerleile K, Aldrovandi A, Francone M, Desch S, Gutberlet M, Strohm O, et al: Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA 2011;306:277–286. 5 Celli BR, MacNee W, Force AET: Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004; 23: 932– 946. 6 Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E: Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J 2006; 27: 1523– 1529.
