Relationship between myocardial oxygenation and blood pressure: Experimental validation using oxygenation-sensitive cardiovascular magnetic resonance

Table 1 Table 2 Background

The relationship between mean arterial pressure (MAP) and coronary blood flow is well described. There is autoregulation within a MAP range of 60 to 140 mmHg providing near constant coronary blood flow. Outside these limits flow becomes pressure-dependent. So far, response of myocardial oxygenation to changes in pressure and flow has been more difficult to assess. While established techniques mostly require invasive approaches, Oxygenation-Sensitive (OS) Cardiovascular Magnetic Resonance (CMR) is a technique that can non-invasively assess changes in myocardial tissue oxygenation. The purpose of this study was to follow myocardial oxygenation over a wide range of blood pressure variation within and outside known coronary autoregulatory limits using OS-CMR, and to relate these data to coronary hemodynamics. Methods

Ten anaesthetized swine (German Large White) underwent left-sided thoracotomy and attachment of a perivascular flow probe to the proximal left anterior descending (LAD) coronary artery for continuous measurement of blood flow (Q LAD ). Thereafter, animals were transferred into a 3T MRI scanner. Mean arterial pressure (MAP) was varied in 10–15 mmHg steps by administering alpha 1 -receptor agents phenylephrine or urapidil. For each MAP level, OS-CMR images as well as arterial and coronary sinus blood gas samples were obtained simultaneously during brief periods of apnea. Relative changes (Δ) of coronary sinus oxygen saturation (ScsO 2 ), oxygen delivery (DO 2 ) and demand (MVO 2 ), extraction ratio (O 2 ER) and excess (Ω) from respective reference levels at a MAP of 70 mmHg were determined and were compared to %change in OS-signal intensity (OS-SI) in simultaneously acquired OS-CMR images.

Q LAD response indicated autoregulation between MAP levels of 52 mmHg (lower limit) and127 mmHg (upper limit). OS-CMR revealed a global myocardial oxygenation deficit occurring below the lower autoregulation limit, with the nadir of OS-SI at -9.0%. With MAP values surpassing 70 mmHg, relative OS-SI increased to a maximum of +10.6%. Consistent with this, ΔScsO 2 , ΔDO 2 , ΔMVO 2 , ΔO 2 ER and ΔΩ responses indicated increasing mismatch of oxygenation balance outside the autoregulated zone. Changes in global OS-CMR were significantly correlated with all of these parameters (p≤0.02) except with ΔMVO 2 . Conclusion

OS-CMR offers a novel and non-invasive route to evaluate the effects of blood pressure variations, as well as of cardiovascular drugs and interventions, on global and regional myocardial oxygenation, as demonstrated in a porcine model. OS-CMR identified mismatch of O 2 supply and demand below the lower limit of coronary autoregulation. Vasopressor induced acute hypertension did not compromise myocardial oxygenation in healthy hearts despite increased cardiac workload and O 2 demand. The clinical usefulness of OS-CMR remains to be established.

Citation: Guensch DP, Fischer K, Jung C, Hurni S, Winkler BM, Jung B, et al. (2019) Relationship between myocardial oxygenation and blood pressure: Experimental validation using oxygenation-sensitive cardiovascular magnetic resonance. PLoS ONE 14(1): e0210098. https://doi.org/10.1371/journal.pone.0210098

Editor: Vincenzo Lionetti, Scuola Superiore Sant’Anna, ITALY

Received: July 29, 2018; Accepted: December 16, 2018; Published: January 16, 2019

Copyright: © 2019 Guensch et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: This work was supported by institutional funds of the Department of Anaesthesiology and Pain Medicine at the Bern University Hospital, Inselspital, University of Bern and the Foundation for Research in Anaesthesiology and Intensive Care Medicine in Bern, Switzerland.

Competing interests: The authors have declared that no competing interests exist. Introduction

Coronary autoregulation

Myocardial blood flow in humans delivers approximately 70-80ml/min/100g myocardial tissue at rest. Coronary flow reserve can increase myocardial blood flow up to 3-5-fold from resting conditions [ 1 – 3 ]. Vascular autoregulation is characteristic for vital organs such as heart and brain, ensuring adequate and near constant tissue blood flow over a wide range of blood pressure [ 4 ]. Thus, blood pressure variation within autoregulatory limits should not compromise delivery of O 2 and nutrients. The main mechanism of blood pressure-dependent regulation of blood flow has been proposed in 1902 by Bayliss [ 5 ], and is known since as the Bayliss effect or myogenic control of vascular tone [ 6 ]. In healthy humans, coronary autoregulation has been reported to be effective within a range of mean arterial pressures (MAP) between approximately 60 and 140mmHg. Such limits may vary with different pathologies, and higher perfusion pressures may be required to maintain constant blood flow [ 7 ]. Especially in the presence of a fixed coronary stenosis or of overriding coronary vasodilation, blood flow becomes pressure dependent [ 8 ].

Coronary perfusion of the left ventricular myocardium mainly occurs during diastole. Hence, an increase in aortic diastolic pressure and a longer diastolic time will improve perfusion. When MAP increases beyond the upper autoregulatory limit, coronary blood flow is markedly increased and becomes pressure dependent. Arterial hypertension will also increase oxygen demand and may reduce subendocardial blood flow [ 9 ]. This can outweigh enhanced oxygen supply from coronary vasodilation. In fact such challenges have been shown to increase oxygen demand and myocardial oxygen extraction [ 2 , 7 – 10 ]. Thus, severe hypertension may uncouple oxygen demand from supply and may compromise myocardial oxygenation. This effect has traditionally been assessed by calculating oxygen supply and demand from invasive blood flow measurements and oximetry of the in- and out-flux blood. Data based on direct measurement of myocardial tissue oxygenation are scarce. Conventional measures of oxygen supply and demand

Myocardial oxygenation depends on the balance of local oxygen supply (DO 2 ) and demand (MVO 2 ) [ 2 , 9 , 11 , 12 ]. Global myocardial oxygenation balance can be assessed by measuring arterial and coronary sinus haemoglobin, its oxygen saturation (ScsO 2 ) and content [ 13 ]. ScsO 2 is obtained invasively, e.g. via a surgically or fluoroscopically placed catheter in the coronary sinus. Oxygen extraction ratio (O 2 ER) is another parameter to describe the relationship between oxygen supply and demand [ 14 ].

DO 2 and MVO 2 are determined by obtaining haemoglobin concentration, blood gas analysis and oximetric status from affluent and effluent blood together with blood flow measurement [ 15 ]. This global approach has the limitation that there is no information about regional supply-demand mismatch. Especially in coronary artery disease, global estimates are insensitive to insufficient blood flow in specific myocardial territories. Regionally resolved blood flow and oxygen content measurement would be required to assess regional oxygenation balance, which are clinically not feasible so far. Direct measurement of tissue oxygen tension or haemoglobin saturation have been proposed and would be preferable, but such methods are also invasive or require probes which are restricted to experimental settings only, for reasons of toxicity [ 16 , 17 ]. Assessment of myocardial oxygenation using cardiovascular magnetic resonance

Oxygenation Sensitive (OS) Cardiovascular Magnetic Resonance (CMR) is a non-invasive technique to map and to follow myocardial oxygenation changes. It uses the Blood Oxygen Level-dependent (BOLD-) effect to generate a contrast in MRI sequences susceptible to this effect. Pauling proposed in 1936 that deoxygenated haemoglobin (dHb) has magnetic properties differing from those in the oxygenated (HbO 2 ) state [ 18 ]. Ogawa was the first to use this mechanism in the field of MRI imaging of the brain and proposed that the paramagnetic effects of dHb disturb magnetic field homogeneity on a molecular level [ 19 ]. This effect accelerates transverse magnetic relaxation through spin-spin interactions in T2- or T2*-sensitive MRI sequences, which decreases signal intensity (SI) in the resulting images. The diamagnetic HbO 2 instead results in weak stabilization of the magnetic field, with no change in SI. While BOLD contrast effects have been utilized in functional MRI scans for long, exploitation of the same effect in the heart for OS-CMR has been developed only more recently [ 20 ]. Today, MR sequences have gained enough spatial and temporal resolution to allow introduction of OS-CMR to human diagnostics. Signal attenuation in OS-CMR images originates in the compartment of the post-capillary myocardial venules [ 21 , 22 ]. Mechanisms that increase dHb concentration, such as diminished oxygen supply (low SaO 2 , decreased blood flow) or increased oxygen extraction (e.g. during increased workload) attenuate local signal intensity (SI). Factors which reduce dHb concentration, like blood flow augmentation or reduction of oxygen demand (luxury perfusion), will enhance OS-signal intensity (SI) and produce regional hyperintensity [ 23 ]. Better regional oxygenation will thus be reflected by ipsi-regional increased SI when compared to a reference image. In contrast to ScsO 2 [ 24 ], OS-CMR is capable to detect also regional oxygenation changes, with a resolution given by the size of the imaged voxels (defined by in-plane resolution and slice thickness, e.g. voxels of 2x2x10mm). SI is not an absolute measurement but must be interpreted as SI change, following a stimulus, in relation to a reference SI […]

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