Is Index of Microvascular Resistance of Sisyphean Utility in Takotsubo Syndrome?

Solberg et al.'s1 assumption, as is generally believed, that coronary microvascular dysfunction (CMD) relates to Takotsubo syndrome (TTS) is unproven. First, only 35% of TTS patients have catheter-based index of microvascular resistance (IMR) of ≥25 within 3 days of hospital admission. Second, the spread of IMR with two outliers in TTS patients is not statistically different from control populations as shown in Solberg et al.'s1 Figure 1A. Third, pre-existing CMD should not be reversible within days. If IMR is a reliable marker for CMD, then CMD is not causative of TTS and vice versa. Further, TTS often recurs spontaneously without triggers suggesting that sympathetic overdrive is not a prerequisite for TTS.2 There are three prevailing conjectures for TTS: (1) multivessel epicardial vasospasm; (2) CMD; and (3) neuroautonomic dysfunction with cardiac β2-adrenoceptor dysregulation. However, the last postulation does not explain the 35% of non-apical TTS found on cardiac magnetic resonance (CMR) imaging. On the other hand, coronary vasoreactivity is usually fleeting, which supports the very low recurrence rate of TTS. Nevertheless, If TTS does relapse it best explains the different variants in the same patient. Failure to provoke vasospasm in asymptomatic convalescent TTS patients beyond 1 week of hospitalization with acetylcholine does not disprove it as the initiator.2 Multivessel epicardial vasospasm is commonly observed acutely during the early phase as reported by Hikaru Sato and Satoshi Kurisu who found the first TTS cases from 1983 and subsequently by others.6 This is analogous to seeing ripples on the pond and not the leaf that falls from the tree. The ‘vasospasm theory’ is reminiscent of the ‘thrombus hypothesis’, that myocardial infarction (MI) is not primarily due to coronary thrombosis since clots are not consistently seen at autopsy. This is in spite of multiple case series, albeit small, where coronary occlusion is detected angiographically, and Klaus P. Rentrop's first successful direct coronary recanalization with guidewire, nitroglycerine and intracoronary thrombolysis in 1979. Until Marcus A. DeWood settles this conundrum by finding thrombotic occlusion in 87% of 126 MI cases during emergency coronary angiography undertaken within 4 hours of symptomatic onset in 1980. This launched intravenous thrombolysis for MI. Prior to that, heparin was used, notably by Paul H. Wood, a celebrated British cardiologist who pioneered catheter laboratory cardiac physiology in 1947. He was a heavy smoker and treated his own left anterior descending (LAD) artery MI with the drug in 1962, aged 54. This unfortunate event was fatal for him and heparin as treatment for MI was proven futile 1 year later in a randomized controlled trial with 40% mortality from Norway, which was replicated the following year in Canada. Incidentally, continuous thermodilution's absolute coronary resistance is notated in his honour, Wood unit, a shorthand for mmHg/mL/min, as will be explained below. IMR can be converted by a factor of 20, that is, IMR of 25 is roughly equivalent to 500 Wood units.7 IMR is a surrogate for microvascular resistance which is the product of coronary perfusion pressure, CPP (distal coronary pressure minus left ventricular end-diastolic pressure; Pd – LVEDP) and mean transit time (Tmn) of a 3 mL saline bolus injected down a coronary artery during adenosine-induced hyperaemia. Flow, Q ∝ 1/Tmn. Hence, the faster a saline bolus travels down an artery, the greater the flow although the reverse may not be true.1 Applying Ohm's law, pressure drives flow against resistance, R: Pd = Q × R; thus, R = Pd/Q. Presupposing that LVEDP and coronary wedge pressure (PW) from collateral circulation are negligible, then IMR = Pd × Tmn.7 From the derivation of IMR, it follows that it has four principal determinants which can spuriously increase it. First, with unobstructed coronary arteries, systemic blood pressure is transmitted unimpeded and it can be labile from anxiety, pain or uncontrolled hypertension; second, coronary artery with discrete lesions or diffuse disease; and third, submaximal hyperaemia from a fixed dose systemic adenosine infusion. In contrast, bolus intracoronary adenosine which is better tolerated, escalating incremental dosing of 200 ug, up to 800 ug in the LAD, allows for rapid study repetitions, and removes any doubt that peak hyperaemia is achieved to confirm an abnormal reading, while being mindful of transient bradycardia and atrioventricular block. Lastly and fourth, left ventricular dysfunction whether systolic (LVSD) or diastolic with raised LVEDP and coronary collateralization will overestimate it because the actual pressure perfusing the microvasculature is lower. IMR is an invasive index that cannot be justifiably repeated clinically. It has poor repeatability and is influenced by multiple confounders; non-coaxial and poorly engaged coronary guide-catheters also give discrepant results in different vessels.4 It has modest predictive value for microvascular obstruction (MVO) on CMR following an anterior (LAD) MI, which should have been its quintessential niche.4 Despite the belief to the contrary, and as alluded to above, it is not independent of epicardial flow rheology, even with Yong's correction for collaterals, as exemplified by an illustrative case in Figure 1, and elsewhere.1 A long stent in the LAD increases IMR, yet coronary flow reserve (CFR) is raised suggesting improved flow.4 It is likely that surface tension drag of stent struts prolongs Tmn, akin to coronary slow flow phenomenon (CSFP).1 Nevertheless, non-invasive CT angiography-derived IMR and other resistance indices will come into play. Although it is counterintuitive how computer modelling of an inexact surrogate makes it reliable. In comparison to bolus thermodilution, continuous thermodilution is a more reproducible method.3, 5 Zeitouni et al.10 undertook this technique in a 73-year-old woman with TTS with severe LVSD due to apical ballooning on CMR and a brain natriuretic peptide (BNP) level seven times the upper limit. Interestingly, they found that her basal coronary microvascular resistance in the LAD was 1096 Wood units. This is a normal value and coupled with an absolute flow rate of 45 mL/min, as per Ohm's equation, gave a mean driving blood pressure of 50 mmHg. As expected, her hyperaemic minimal microvascular resistance, Rμ was 751 (<500) Wood units, or an equivalent IMR of 38. An elevated LVEDP above 17 mmHg if adjusted for, would lower the IMR to under threshold of 25. With a hyperaemic flow of 84 mL/min, the CFR was 1.8 (≥2), microvascular resistance reserve, MRR 1.5 (≥2.1, or 2.7 for a more generous upper limit), and together with a high Rμ (IMR); fulfilled the current definition for CMD. Cut and dried, case closed? But dive and delve a little bit deeper, she was hypotensive with a raised LVEDP, her CPP was well under 50 mmHg, which meant that her autoregulatory range was breached during the procedure. Thus, a low coronary flow state. The raised Rμ was due to an elevated LVEDP. In other words, low CPP from hypotension and raised LVEDP mimics CMD. Six weeks later, she had a restudy, her basal coronary resistance was similar at 964 Wood units. Both rest and hyperaemic flow increased with lowering of her Rμ. These findings suggest that her blood pressure rose and LVEDP fell, giving her an effective CPP, restoring her autoregulatory capacity. This timely, expedient and detailed case study indicates that CMD in TTS is in fact artefactual from haemodynamic instability and explains the transitory nature of ‘CMD’ in TTS.3 Therefore, CMD cannot be diagnosed during acute TTS. Provocatively, CMD is not a driver, nor has it an aetiological basis in TTS. Although conceivably pre-existing CMD can be a facilitator but most TTS patients are asymptomatic preceding their presentation, meaning that CMD is not common in this population. Finally, coronary physiology should be assessed in conjunction with cardiac function, which does not appear to be the case in TTS or acute MI studies.4, 9 This is crucial since LVEDP is the key component of CPP in the setting of LVSD, and as a corollary in MI, LV unloading reduces infarct size by promoting myocardial perfusion.8

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.