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In which case CMD is a transient epiphenomenon that also convalesces with resolution of left ventricular dysfunction. To test this hypothesis a detailed coronary physiology study with accurate flow measurement is required as illustrated by the ensuing case.
A 57-year-old woman was involved in a train crash 1 year previously. Then she had chest pain and transient left bundle branch block (LBBB) without significant troponin leak. Her coronary arteries were unobstructed and left ventricle on angiogram showed apical ballooning with a raised end-diastolic pressure (LVEDP) of 25 mmHg consistent with TTS. Her cardiac magnetic resonance scan at one month found a normalised heart without left ventricular hypertrophy. However, she continues to suffer angina and breathlessness. She now has persistent LBBB and her symptoms are exacerbated by recent death of a sibling. She is not on oestrogen replacement therapy. She is an ex-smoker and takes only an ACE inhibitor.
A coronary physiology study was undertaken. Her central aortic blood pressure and LVEDP were recorded with a 4-French pigtail catheter. These were 130/80 mmHg and 5 mmHg respectively. The latter did not rise with handgrip excluding diastolic dysfunction. Next, a 5-French EBU3.5 catheter subselected her circumflex artery thus it was studied using the continuous thermodilution technique which is a highly reproducible method.
The following were obtained; hyperaemic flow 220 mL/min and minimal resistance, Rμ 337 (< 500) Wood Units; baseline flow 126 mL/min and resting resistance R 729 Wood Units. The coronary flow reserve (CFR) was 1.75 (220/126) (> 2.5) which signifies CMD if taken alone. The better known index of microvascular resistance (IMR) derived from adenosine-induced hyperaemia and bolus thermodilution is well correlated with Rμ by a factor of 20; so it would be 17 (< 25).
Intracoronary acetylcholine 20 ug, 40 ug and 80 ug boluses were given. There was a dose-dependent increase in epicardial vasospasm with corresponding distal-to-proximal pressure gradient, Pd/Pa of 0.86, 0.79 and 0.58 culminating in subtotal-occlusion provoking angina but without electrocardiographic ischaemia (Figure).
There are 3 salient observations. First, she does not have CMD since she has low hyperaemic and baseline resistance suggesting a vasodilated resting state accordingly her reduced CFR is normal for her. This might be due to ACE inhibition. Second, she has normal microvascular endothelial function because her flow increases by at least 50% with low dose acetylcholine. Third, she has acetylcholine-induced epicardial vasospasm implying epicardial endothelial dysfunction which could explain her continuing symptoms. In conclusion, this woman has endothelial dysfunction isolated to the epicardial vasculature sparing the microvasculature. Consequently, epicardial vasospasm could be her TTS Trigger supporting the notion that CMD might be a secondary phenomenon.
Acetylcholine provokes a dose-dependent epicardial vasospasm in a woman with convalescent Takotsubo Syndrome.
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Intact microvasculature with preserved endothelial function mitigates within its autoregulatory range any potential flow reduction due to epicardial vasospasm.
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Isolated reduced coronary flow reserve should be interpreted cautiously as it could be normal if the coronary resistance is low.
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Conversely, a high coronary resistance could be due to high left ventricular filling pressure of any aetiology, e.g. hypertension, diabetes, myocardial infarction, etc.
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The diagnosis of coronary microvascular dysfunction should take into account both coronary resistance and left ventricular function.
Ethics Statement
Case reported has adhered to the relevant ethical guidelines. Patient informed consent was obtained prior to publication of this report.
FigurePanel A – Unobstructed circumflex artery, Panel B – Baseline indices at unity with fractional changes in flow and resistance in hyperaemia, and in response to acetylcholine. The low baseline absolute resistance indicates a vasodilated resting state using up part of the vasodilatory reserve. Therefore the apparently reduced vasodilatory capacity or CFR <2.5 is normal in this context. Further, lower doses of acetylcholine although caused epicardial vasospasm, the flow increased (>1.5) and resistance fell suggesting intact microvascular endothelial function. Whilst the severe epicardial vasospasm with high dose acetylcholine exceeded the microvascular autoregulatory range causing flow to fall precipitously precipitating angina, Panel C,D & E – Progressive epicardial vasospasm with increasing acetylcholine doses. Falling Pd/Pa (Pd – distal mean pressure, Pa – proximal mean pressure) ratios as epicardial vasospasm worsened but flow increased in the first 2 doses due to preserved microvascular endothelial function, until failure of microvascular autoregulation to compensate for the severe epicardial vasospasm with high dose acetylcholine.
The author has no conflicts of interest to disclose.
Funding Sources
None.
Acknowledgements
The author thanks the Department of Cardiology as led by Drs Rajan Sharma and Manav Sohal, Cardiac Catheter Laboratory Leaders: Mary Keal (Matron), Clare Oneill (Cardiac Physiology), Jaysson Crussis and Dinesh Sajnani (Cardiac Radiography). Dr Hasan Qaisar (Trainee) who assisted in the case, the Departmental and Cardiac Catheter Laboratory auxillary and nursing staff involved in caring for the patient. The patient herself who fully trusted the team and consented to having her case used for medical learning and communication. Last but not least, Christopher M. Brown, founder of Cormed Ltd, who graciously without conditions donated some equipment to support the Coronary Physiology Programme.
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