Tako-Tsubo (Stress) Cardiomyopathy: Pathophysiology and Natural History

Tako-Tsubo (Stress) Cardiomyopathy: Pathophysiology and Natural HistoryBy
For The Degree Of Doctor of Philosophy
Faculty of Health Science School of Medicine
The University of Adelaide
Introduction. Tako-Tsubo cardiomyopathy (TTC), also known as apical ballooning
syndrome, is a recently described form of acute cardiac dysfunction of uncertain
pathogenesis, which occurs with greatest frequency among post-menopausal women.
Presentation generally mimics that of an acute myocardial infarction (AMI) but is
independent of the presence of fixed coronary artery disease and is classically preceded by
severe stress. While patients with TTC with ST elevation are typically diagnosed at
emergent cardiac catheterization, the majority does not exhibit initial ST elevation. It is
not known whether TTC can be reliably distinguished for AMI non-invasively on the basis of
clinical and laboratory tests. Although there is considerable uncertainty about the
pathogenesis of TTC, pronounced catecholamine release and an acute inflammatory
process are implicated. Systolic dysfunction most commonly affects the apex of the left
ventricle and has generally been considered self-limiting and fully reversible. Although
obvious hypokinesis resolves and left ventricular ejection fraction tends to return to
normal, data that challenge this view include abnormal elevation of natriuretic peptide
concentrations, 3 months from the index event, together with the late
persistence of some inflammatory cells on LV biopsy.
Methods. In three experimental chapters, this thesis examines aspects of (a) diagnosis (b)
pathogenesis and (c) recovery, in a cohort of 125 TTC patients (mean age 67 years; 95%
female). As regards diagnosis, it was hypothesized that an arbitrarily derived ‘TTC score’,
incorporating NT-proBNP levels, might facilitate early differentiation from a cohort of
females with AMI (n = 56; mean age 70 years). The primary comparison was based on data
available at 24 hours post-admission. In a subset of 49 TTC patients, acute multisequential
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cardiac magnetic resonance imaging was performed and repeated at 3 months.
Pathogenetic investigations:- Extent of oedema was quantified both regionally and
globally from T2 weighted images, with comparison to data from 10 age-matched female
controls. Correlations were sought between oedema and the extent of hypokinesis,
catecholamine release, N-terminal proBNP release and markers of systemic inflammatory
activation. Functional recovery was assessed via 2D speckle-tracking echocardiography (n =
36) and 15 patients, ≥1 year from their index TTC admission, underwent T1 mapping via
CMR in order to address the question of whether residual fibrosis is present after TTC.
Results.
A. Diagnosis: TTC scores were significantly different (TTC group median was 4, vs. 2 in the
ACS group; P < 0.0001). Receiver operator curve analysis demonstrated an area under the
curve (AUC) of 0.74 (P < 0.0001), with 62% sensitivity and 75% specificity for a score ≥4;
when stressor exposure was scored in both groups, AUC was 0.89 (P<0.0001), with 78%
sensitivity and 82% specificity (TTC score ≥4). The TTC score separated groups when
haemodynamic compromise was absent (AUC 0.80, P<0.0001), but not when hypotension
or heart failure were evident (P = NS).
B. Pathogenesis: In the acute phase of TTC, T2-weighted signal intensity was greater at the
apex than at the base (P < 0.0001) but was nevertheless significantly elevated at the base
(P < 0.0001), relative to control values; over three months, T2-weighted signal decreased
substantially but remained abnormally elevated (P = 0.02). Regional extent of edema
correlated inversely with radial myocardial strain. There were also direct correlations
between global T2-weighted signal and plasma normetanephrine (r=0.33, p=0.028), peak
NT-proBNP (r=0.40, p=0.0045), C-reactive protein (r=0.34, p=0.023) and troponin T release
(r=0.29, p=0.045).
C. Recovery: Patients exhibited lower global longitudinal strain than controls [mean 17.9 ±
3.1 (SD)%, versus 20.3 ± 1.6; P = 0.0057], but did not differ significantly from controls in
values of apical twist. Three month global longitudinal strain correlated with the extent of
residual NT-pro-BNP elevation (r=0.38, P=0.027), but did not correlate with markers of the
acute severity of the TTC attack. Finally, patients with a remote history of TTC,
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demonstrated significant intramyocardial fibrosis (Ve = 0.24), versus controls (Ve = 0.21, P =
0.013), but extent of which was not correlated with global longitudinal strain.
Conclusions. (1) The TTC score, while not of itself diagnostic, may facilitate the
differentiation of TTC in patients with presumed ACS, but with diminished efficacy in the
presence of haemodynamic compromise. (2) TTC is associated with slowly resolving global
myocardial edema, the acute extent of which is correlated with regional contractile
disturbance and acute release of both catecholamines and NT-proBNP. (3) Imaging data
after TTC indicate that, at 3 months, recovery is substantial, but not complete; at ≥1 year
there is evidence of diffuse interstitial myocardial fibrosis. Further efforts to expedite
diagnosis, delineate pathogenesis and evaluate residual disability may assist in the
development of appropriate treatment regimens.
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Declaration
This thesis is the result of my own investigation, except where otherwise stated. It
contains no material which has been accepted for the award of any other degree or
diploma in any university or other tertiary institution and, to the best of my knowledge and
belief, contains no material previously published or written by another person, except
where due reference has been made in the text. In addition, I certify that no part of this
work will, in the future, be used in a submission for any other degree or diploma in any
university or other tertiary institution without the prior approval of the University of
Adelaide and where applicable, any partner institution responsible for the joint-award of
this degree.
I give consent to this copy of my thesis when deposited in the University Library, being
made available for loan and photocopying, subject to the provisions of the Copyright Act
1968. The author acknowledges that copyright of published works contained within this
thesis resides with the copyright holder(s) of those works.
I also give permission for the digital version of my thesis to be made available on the web,
via the University's digital research repository, the Library catalogue, and also through web
search engines, unless permission has been granted by the University to restrict access for
a period of time.
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Acknowledgements
I am truly indebted and thankful to Professor John Horowitz for his help in generating
ideas, support and guidance throughout. I would also like to acknowledge A/Prof
Christopher Zeitz, who, as well as co-supervising this project, took a leading role among
cardiologists at The Queen Elizabeth and Lyell McEwen Hospitals in recruiting patients for
this study.
My colleagues, Dr Thanh Ha Nguyen, Dr Yuliy Chirkov, Ms Jeanette Stansborough and Ms
Angela Kucia have all been of great assistance in the TTC project, with both intellectual
contributions as well as involvement in the day-to-day work of the study.
This thesis relied heavily on cardiac imaging personnel: in this regard, notable thanks goes
to Ms Sue Collings, Mr David Lockyer, Ms Kerry Williams, Ms Tharshy Pasupathy, Mr
Matthew Chapman, Mr Brett Stocker, Dr Betty Raman, Dr Devan Mahadevan, Professor
John Beltrame and Dr Ewan Choo.
I would like to thank the National Health and Medical Research Council and for funding this
work and, similarly, the generosity of numerous patients and controls in giving their time
for the studies described herein.
Finally, I would like to thank my wife, Sally, and children, Ella, Jonah, Daisy and Shiloah, for
their support, patience and understanding.
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Statement of contribution to research
The studies were conceived and designed jointly by Professor Horowitz and myself.
Execution
I performed all the recruitment and organization of patients into the studies, with the
assistance of Ms Jeanette Stansborough (research nurse). I collected all clinical data, also
with assistance from Ms Stansborough. I performed echocardiographic studies and cardiac
magnetic resonance scans at The Queen Elizabeth Hospital. Dr Yuliy Chirkov performed
the platelet aggregometry studies. Metanephrine assays were performed by Dr Malcolm
Whiting at SA Pathology, Adelaide. Collagen biomarker assays was performed by Dr
Michael Metz at ClinPath, Adelaide.
Analysis
All data were collated and analyzed by myself. Inter-observer analyses were performed
with Dr Thanh Ha Nguyen, Mr Matthew Chapman and Ms Tharshy Pasupathy.
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List of published studies
This thesis is based in part on the following original studies, which exist in published form:
1. Nguyen TH, Neil CJ, Sverdlov AL, et al. N-terminal pro-brain natriuretic protein
levels in takotsubo cardiomyopathy. The American Journal of Cardiology 2011, 108,
1316-1321.
2. Neil CJ, Nguyen TH, Sverdlov AL, et al. Can we make sense of takotsubo
cardiomyopathy? An update on pathogenesis, diagnosis and natural history. Expert
Rev Cardiovasc Ther 2012, 10, 215-221.
3. Neil CJ, Nguyen TH, Kucia A, et al. Slowly resolving global myocardial
inflammation/oedema in Tako-Tsubo cardiomyopathy: evidence from T2-weighted
cardiac MRI. Heart 2012, 98, 1278-1284.
4. Neil CJ, Chong CR, Nguyen TH, Horowitz JD: Occurrence of Tako-Tsubo
cardiomyopathy in association with ingestion of serotonin/noradrenaline reuptake
inhibitors. Heart, Lung & Circulation 2012, 21, 203-205.
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List of Tables ....................................................................................................... 15
List of Figures ...................................................................................................... 16
Acute myocardial injury: ischaemic and non-ischaemic causes ........................... 19 1.1
Tako-Tsubo cardiomyopathy as a non-ischaemic acute cardiac injury ................. 20 1.2
1.2.1 Historical aspects ................................................................................................ 22
1.2.3 Evolution of definition ........................................................................................ 23
1.2.3.1 The problem of ‘mandatory’ cardiac catheterization ...................................................... 24
1.2.3.2 Is exclusion of fixed coronary disease enough?............................................................... 25
1.2.3.3 Can TTC coexist with CAD, phaeochromocytoma or myocarditis? .................................. 25
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1.2.3.4 Excluding an ischaemic basis for regional contractile dysfunction in TTC .......................27
Tako-Tsubo cardiomyopathy: clinical aspects ..................................................... 28 1.3
1.3.1 Epidemiology ...................................................................................................... 28
1.3.2.3 Antecedent psychological and physiological stress in TTC ..............................................31
1.3.2.4 TTC complicating medical/surgical illness ........................................................................31
Associated abnormalities .................................................................................. 34 1.4
1.4.1.1 ST-T wave abnormalities: specificity for TTC ...................................................................34
1.4.1.2 QT prolongation and torsade de pointes .........................................................................34
1.4.2 Laboratory findings............................................................................................. 36
1.4.2.2 Natriuretic peptide elevation...........................................................................................36
1.4.3 Echocardiography ............................................................................................... 42
1.4.3.1 Doppler echocardiography ..............................................................................................43
1.4.3.2 Diastolic function .............................................................................................................44
1.4.4.1 Evaluation of myocardial necrosis or scar .......................................................................48
1.4.4.2 Oedema imaging ..............................................................................................................49
1.4.5.1 Nuclear perfusion imaging ...............................................................................................50
1.4.5.2 Cardiac sympathetic neuroimaging .................................................................................51
1.4.5.3 “Metabolic” imaging findings ..........................................................................................51
1.5.1.1 Anatomical problems .......................................................................................................52
1.5.2 Is there a problem with myocardial perfusion? ................................................. 56
1.5.2.1 Diffuse or multivessel epicardial coronary spasm ...........................................................57
1.5.2.2 Coronary reserve and microvascular dysfunction ...........................................................57
1.5.3 Biochemical bases of hypokinesis: calcium, energetics and stunning ............... 59
1.5.4 Does catecholamine exposure “cause” TTC? ..................................................... 61
1.5.4.1 “Non-classical” actions of catecholamines: oxidative stress ...........................................62
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1.5.5.1 Neuropeptide Y ............................................................................................................... 64
1.5.5.2 Nitric oxide ...................................................................................................................... 64
1.5.6 Factors engendering rapid recovery: biochemical determinants ....................... 66
1.5.7 Relevance of postulated animal models ............................................................. 67
1.5.7.1 Observations from rodent models of catecholamine cardiotoxicity ............................... 67
1.5.7.2 Application to TTC: rodent models .................................................................................. 68
1.5.7.3 A non-human primate model of TTC ............................................................................... 73
1.5.8 Key unanswered questions ................................................................................. 73
1.5.8.1 Insights into predisposition in females ............................................................................ 73
1.5.8.2 What underpins individual susceptibility to TTC? ........................................................... 75
1.5.8.3 Basis for acute hemodynamic heterogeneity .................................................................. 77
1.5.9 Potential links to other forms of acute cardiomyopathy .................................... 78
Natural history of Tako-Tsubo cardiomyopathy .................................................. 81 1.6
1.6.1 Short-term complications and outcomes ........................................................... 81
1.6.1.1 Acute complications of TTC ............................................................................................. 81
1.6.1.2 Haemodynamic status in TTC .......................................................................................... 82
1.6.2 Long term outcome............................................................................................. 83
Tables .............................................................................................................. 86 1.9
Figures ........................................................................................................... 93 1.10
Chapter 2: Clinical Studies in TTC: Towards Expedited Diagnosis ........................ 96
Background ...................................................................................................... 97 2.1
2.1.2 Potential components of a diagnostic algorithm: candidates ............................ 99
2.1.3 A summative “TTC score” for early diagnosis of TTC? ...................................... 102
2.1.4 Development of a ‘TTC score’ ........................................................................... 102
2.1.5 Aims and Hypotheses ....................................................................................... 103
Methodology .................................................................................................. 103 2.2
2.2.4 Investigations .................................................................................................... 105
2.2.4.3 ECG analysis and definitions ......................................................................................... 107
2.2.4.4 Clinical imaging ............................................................................................................. 107
2.2.6 Statistical methodology .................................................................................... 109
2.3.2 Clinical outcomes in TTC and ACS .................................................................... 110
2.3.3 Haemodynamic and imaging findings in TTC ................................................... 111
2.3.4 Long-term follow-up ........................................................................................ 111
2.3.5 Presenting ECG and biomarker findings in TTC, versus ACS ............................ 112
2.3.6 NT-proBNP in TTC versus ACS .......................................................................... 113
2.3.6.1 Diagnostic utility of NT-proBNP: effect of haemodynamic status ................................ 113
2.3.6.2 Diagnostic utility of NT-proBNP: effect of ST-elevation................................................ 114
2.3.7 Effectiveness of TTC score ................................................................................ 114
2.3.7.1 Effectiveness of TTC score: effect of haemodynamic status ........................................ 115
2.3.7.2 Effectiveness of TTC score: effect of ST-elevation ........................................................ 115
2.3.8 Optimization of NT-proBNP thresholds: sensitivity and specificity ................. 115
Discussion ...................................................................................................... 116 2.4
2.4.2 Additional clinical data ..................................................................................... 117
2.4.3 ECG patterns in TTC versus ACS ....................................................................... 118
2.4.4 NT-proBNP elevation in TTC versus TTC ........................................................... 119
2.4.5 The TTC score: potential for expedited diagnosis ............................................ 120
2.4.6 Limitations ........................................................................................................ 121
Tables............................................................................................................. 124 2.6
Chapter 3: Inflammatory activation during the acute phase of Tako-Tsubo
cardiomyopathy: information from cardiac magnetic resonance ........................ 135
Introduction ................................................................................................... 136 3.1
Methodology .................................................................................................. 137 3.2
3.2.5 Control subject selection .................................................................................. 139
3.2.6 Cardiac magnetic resonance imaging ............................................................... 139
3.2.7 T2-weighted signal quantitation methodology ................................................. 140
3.2.8 Global and regional wall motion quantitation .................................................. 142
3.2.9 Statistics ............................................................................................................ 142
Results ........................................................................................................... 143 3.3
3.3.3 Correlates of corrected T2-w values ................................................................. 145
Discussion ...................................................................................................... 146 3.4
3.4.2 Implications of persistent/slowly resolving oedema in TTC ............................. 148
3.4.3 Implications for pathogenesis: demonstration of catecholamine effect ......... 148
3.4.4 NT-proBNP and troponin elevation in relation to underlying oedema ............ 149
3.4.5 Markers of systemic inflammation in relation to cardiac oedema ................... 150
3.4.6 Limitations ........................................................................................................ 150
Conclusions .................................................................................................... 151 3.5
Tables ............................................................................................................ 152 3.6
Figures ........................................................................................................... 154 3.7
Chapter 4: Recovery from TTC: short and long-term aspects. ........................... 160
Introduction ................................................................................................... 161 4.1
4.1.1 Evaluation of subtle LV dysfunction and fibrosis: imaging tools ...................... 162
4.1.2 Aims and hypotheses ........................................................................................ 163
Methodology .................................................................................................. 164 4.2
4.2.2.1 Serial protocol and analysis ........................................................................................... 165
4.2.2.2 Multidirectional deformation and rotational parameters ............................................ 166
4.2.2.3 Non-2DS echocardiographic parameters ...................................................................... 167
4.2.3 Additional biological investigations (Study 1) ................................................... 168
4.2.4 CMR methodology ............................................................................................ 168
4.2.4.1 Scanning protocol .......................................................................................................... 168
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4.2.5 Statistics ........................................................................................................... 172
Results ........................................................................................................... 172 4.3
4.3.2.1 Serial echocardiographic indices and time-course of recovery .................................... 173
4.3.2.2 3-month values of nominated 2DS indices, versus controls (Hypothesis 1a) ............... 173
4.3.2.3 Acute-phase determinants of residual deficit in global longitudinal strain (Hypothesis 1b)
174
4.3.3 Results of Study 2 ............................................................................................. 174
4.3.3.1 Evidence of myocardial fibrosis at ≥ 1 year (Hypothesis 2a) ........................................ 175
4.3.4 Correlates of extent of myocardial fibrosis at ≥ 1 year (Hypothesis 2b) .......... 175
Discussion ...................................................................................................... 175 4.4
4.4.1 Non-deformational parameters in acute and recovery phases (Study 1) ........ 176
4.4.2 Deformational parameters in acute and recovery phases (Study 1) ............... 176
4.4.3 Subtotal LV recovery in TTC and its correlates (Hypotheses 1a, 1b and 1c) .... 177
4.4.4 Myocardial fibrosis in TTC and its correlates (Study 2) .................................... 178
4.4.5 Post-mortem findings in support of post-TTC myocardial fibrosis .................. 179
4.4.6 Limitations ........................................................................................................ 180
Chapter 5: Conclusions and future perspectives ................................................ 196
Summary: major findings ................................................................................ 197 5.1
Implications of these findings .......................................................................... 198 5.2
Key unresolved issues related to the current thesis .......................................... 199 5.3
Potential means addressing these unresolved issues ........................................ 201 5.4
Priorities in advancing the understanding of TTC: ............................................. 203 5.5
References ......................................................................................................... 206
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Table 1.2 Mayo Clinic diagnostic criteria for Tako-Tsubo cardiomyopathy .................. 87
Table 1.3 Common or salient stressors/precipitants* of TTC ....................................... 88
Table 1.4 Major pathogenetic theories in TTC .............................................................. 89
Table 1.5 Important seven-transmembrane-spanning receptors ................................. 90
Table 1.6 Histological and ultrastructural findings in patients with acute TTC ............. 90
Table 1.7 Case-control studies examining sympathetic responsiveness in TTC ............ 91
Table 1.8 Cases of TTC/shock, with rapid improvement on Levosimendan .................. 92
Table 1.9 Precipitation of TTC with dobutamine: selected case reports ...................... 92
Table 2.1 Comparison of acute clinical and angiographic features ............................. 124
Table 2.2 Classification of identified antecedent stressors in TTC group .................... 125
Table 2.3 Haemodynamic and imaging characteristics of TTC patients ...................... 126
Table 2.4 Comparison of acute biochemical and ECG features ................................... 127
Table 2.5 Evolution of selected ECG findings in TTC .................................................... 128
Table 2.6 Contribution of extent of NT-proBNP elevation to potential discrimination
between TTC and ACS. ............................................................................................. 129
Table 3.1 Patient and control characteristics, Studies 1 and 2.................................... 152
Table 3.2 CMR findings: LV volumes and functional indices ....................................... 153
Table 4.1 Phantom manufacture according to specified T1 and T2 times .................. 184
Table 4.2 Clinical and laboratory features in patients and controls ............................ 185
Table 4.3 Non-deformational parameters of LV function ........................................... 186
Table 4.4 Longitudinal and rotational parameters of LV function .............................. 187
Table 4.5 Radial and circumferential deformational indices ....................................... 188
Table 4.6 CMR indices for Study 2 ............................................................................... 189
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List of Figures
Figure 1.1 Selected examples from the cardiac imaging of TTC .................................... 93
Figure 1.2 Microvascular function in TTC. ..................................................................... 94
Figure 1.3 Representative haemodynamic findings in "obstructive TTC" ..................... 95
Figure 2.1 Discriminatory value of extent of NT-proBNP elevation in TTC ................. 130
Figure 2.2 Discriminatory value of NT-proBNP in relation to ST-elevation ................. 131
Figure 2.3 Discriminatory value of TTC scores ............................................................. 132
Figure 2.4 Value of TTC scores with respect to haemodynamic status ....................... 133
Figure 2.5 Discriminatory value of TTC scores with respect to ST-elevation .............. 134
Figure 3.1 Example T2-weighted short axis images ..................................................... 154
Figure 3.2 T2-w SI data from normal controls and acute TTC patients ........................ 155
Figure 3.3 Colour-coded bull’s-eye plots of T2-w SI in TTC versus controls ................. 156
Figure 3.4 Acute and 3 month T2-w SI compared by ANOVA ...................................... 157
Figure 3.5 Peak radial strain versus corrected T2-w SI, by region ................................ 158
Figure 3.6 Acute phase correlations between global T2-w SI and plasma
normetanephrine, NT-proBNP, troponin T and C-reactive protein......................... 159
Figure 4.1 Phantom validation of MOLLI-derived T1 values ........................................ 184
Figure 4.2 Measurement and reproducibility characteristics of main indices. ........... 189
Figure 4.3 Recovery of LV functional indices ............................................................... 190
Figure 4.4 Comparison of LV function 3-month post-TTC, versus controls ................. 191
Figure 4.5 Relationship between global longitudinal strain with LV mass. ................. 192
Figure 4.6 Relationship between global longitudinal strain and NT-proBNP concentration
at 3 months .............................................................................................................. 192
Figure 4.7 Comparison of Ve in TTC patients versus age-matched controls ................ 193
Figure 4.8 Selected postmortem histological images .................................................. 194
Figure 4.9 Further histological depiction of intramyocardial fibrosis .......................... 195
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MI Myocardial Infarction STEMI ST-Elevation Myocardial Infarction NSTEMI Non-ST-Elevation Myocardial Infarction TTC Tako-Tsubo Cardiomyopathy ACS Acute Coronary Syndrome LV Left Ventricle CAD Coronary Artery Disease TIA Transient Ischaemic Attacks ANP Atrial Natriuretic Peptide BNP; NT-proBNP B-Type Natriuretic Peptide; Amino-Terminal Prohormone Of BNP ET-1 Endothelin 1 NPR-C Natriuretic Peptide Receptor C cGMP Cyclic Guanosine Monophosphate AR; βAR Adrenoceptor; Beta-Adrenoceptor SR Sarcoplasmic Reticulum SERCA Sarco(Endo)Plasmic Reticulum Calcium ATPase NET Norepinephrine Transporter COMT Catecholamine O-Methyl Transferase MAO Monoamine Oxidase VMA Vanillylmandelic Acid HPLC High Performance Liquid Chromatography LVEF Left Ventricular Ejection Fraction WMSI Wall Motion Score Index PCWP Pulmonary Capillary Wedge Pressure LGE Late Gadolinium Enhancement CMR; CE-CMR Cardiovascular Magnetic Resonance; Contrast-Enhanced CMR SPECT Single Photon Emission Computed Tomography SNT Sympathetic Nerve Terminal LVOT Left Ventricular Outflow Tract LAD Left Anterior Descending PDA Posterior Descending Artery NOS Nitric Oxide Synthase Pl3K Phosphoinositide 3-Kinase PKB Protein Kinase B PARP Poly-ADP Ribose Polymerase GRK5 G Protein-Coupled Receptor Kinase 5 LPS Lipopolysaccharide TNF-α Tumour Necrosis Factor Alpha IL Interleukin SPAIR SPectral Attenuated Inversion Recovery SENSE SENSitivity Encoding T2-W SI T2-Weighed Signal Intensity 2DS 2D-speckle tracking Ve Extracellular volume
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Chapter 1
Acute myocardial injury: ischaemic and non-ischaemic causes 1.1
Within contemporary medicine, perhaps no single condition has as great an impact on
global health, or has prompted so concentrated a research effort, than acute myocardial
infarction (MI) (Murray and Lopez, 1997, Ferreira, 2010). Although descriptions of other
manifestations of ischaemic heart disease, such as angina pectoris (Heberden, 1772),
preceded it, the first descriptions of acute MI emerged independently from two Russian
authors in 1910 (Obraztsov and Strazhesko, 1910) and from Herrick, who in 1912 observed
clinical and electrocardiographic…