Dominik P. Guensch

Breathing manoeuvre-dependent changes in myocardial oxygenation in healthy humans

AIMS CO₂ is an intrinsic vasodilator for cerebral and myocardial blood vessels. Myocardial vasodilation without a parallel increase of the oxygen demand leads to changes in myocardial oxygenation. Because apnoea and hyperventilation modify blood CO₂, we hypothesized that voluntary breathing manoeuvres induce changes in myocardial oxygenation that can be measured by oxygenation-sensitive cardiovascular magnetic resonance (CMR). METHODS AND RESULTS Fourteen healthy volunteers were studied. Eight performed free long breath-hold as well as a 1- and 2-min hyperventilation, whereas six aquatic athletes were studied during a 60-s breath-hold and a free long breath-hold. Signal intensity (SI) changes in T₂*-weighted, steady-state free precession, gradient echo images at 1.5 T were monitored during breathing manoeuvres and compared with changes in capillary blood gases. Breath-holds lasted for 35, 58 and 117 s, and hyperventilation for 60 and 120 s. As expected, capillary pCO₂ decreased significantly during hyperventilation. Capillary pO₂ decreased significantly during the 117-s breath-hold. The breath-holds led to a SI decrease (deoxygenation) in the left ventricular blood pool, while the SI of the myocardium increased by 8.2% (P = 0.04), consistent with an increase in myocardial oxygenation. In contrast, hyperventilation for 120 s, however, resulted in a significant 7.5% decrease in myocardial SI/oxygenation (P = 0.02). Change in capillary pCO₂ was the only independently correlated variable predicting myocardial oxygenation changes during breathing manoeuvres (r = 0.58, P < 0.01). CONCLUSION In healthy individuals, breathing manoeuvres lead to changes in myocardial oxygenation, which appear to be mediated by CO₂. These changes can be monitored in vivo by oxygenation-sensitive CMR and thus, may have value as a diagnostic tool.

Response of myocardial oxygenation to breathing manoeuvres and adenosine infusion.

AIMS Testing for inducible myocardial ischaemia is one of the most important diagnostic procedures and has a strong impact on clinical decision-making. Current standard protocols are typically limited by the required infusion of vasodilatory substances. Recent data indicate that changes of myocardial oxygenation induced by hyperventilation and breath-holds can be monitored by oxygenation-sensitive (OS) cardiovascular magnetic resonance (CMR) and may be useful for assessing coronary vascular function. As tests using breathing manoeuvres may be safer, easier, and more comfortable than vasodilator stress agent infusion, we compared its impact on myocardial oxygenation with that of a standard adenosine infusion protocol. METHODS AND RESULTS In 20 healthy volunteers, we assessed changes of myocardial oxygenation using OS-CMR at 3 T during adenosine infusion (140 µg/kg/min, i.v.) and during voluntary breathing manoeuvres: a maximal breath-hold following normal breathing and a maximal breath-hold following 60 s of hyperventilation. The study was successfully completed in 19 subjects. There was a significantly stronger myocardial response for hyperventilation (decrease of -10.6 ± 7.8%) and the following breath-hold (increase of 14.8 ± 6.6%) than adenosine (3.9 ± 6.5%), whereas a simple maximal voluntary breath-hold yielded a similar signal intensity increase (3.1 ± 3.9%). Subjective side effects occurred significantly more often with adenosine, especially in females. CONCLUSIONS Hyperventilation combined with a subsequent long breath-hold and hyperventilation alone both have a greater impact on myocardial oxygenation changes than an intravenous administration of a standard dose of adenosine, as assessed by OS-CMR. Breathing manoeuvres may be more efficient, safer, and more comfortable than adenosine for the assessment of the coronary vasomotor response.

Hyperoxia Exacerbates Myocardial Ischemia in the Presence of Acute Coronary Artery Stenosis in Swine

Background—Current guidelines limit the use of high oxygen tension after return of spontaneous circulation after cardiac arrest, focusing on neurological outcome and mortality. Little is known about the impact of hyperoxia on the ischemic heart. Oxygen is frequently administered and is generally expected to be beneficial. This study seeks to assess the effects of hyperoxia on myocardia oxygenation in the presence of severe coronary artery stenosis in swine. Methods and Results—In 22 healthy pigs, we surgically attached a magnetic resonance compatible flow probe to the left anterior descending coronary artery (LAD). In 11 pigs, a hydraulic occluder was inflated distal to the flow probe. After increasing PaO2 to >300 mm Hg, LAD flow decreased in all animals. In 8 stenosed animals with a mean fractional flow reserve of 0.64±0.02, hyperoxia resulted in a significant decrease of myocardial signal intensity in oxygenation-sensitive cardiovascular magnetic resonance images of the midapical segments of the LAD territory. This was not seen in remote myocardium or in the other 8 healthy animals. The decreased signal intensity was accompanied by a decrease in circumferential strain in the same segments. Furthermore, ejection fraction, cardiac output, and oxygen extraction ratio declined in these animals. Changing PaCO2 levels did not have a significant effect on any of the parameters; however, hypercapnia seemed to nonsignificantly attenuate the hyperoxia-induced changes. Conclusions—Ventilation-induced hyperoxia may decrease myocardial oxygenation and lead to ischemia in myocardium subject to severe coronary artery stenosis.

Relationship of vasodilator-induced changes in myocardial oxygenation with the severity of coronary artery stenosis: a study using oxygenation-sensitive cardiovascular magnetic resonance

AIMS To explore the impact of the functional severity of coronary artery stenosis on changes in myocardial oxygenation during pharmacological vasodilation, using oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR) imaging and invasive fractional flow reserve (FFR). An FFR is considered a standard of reference for assessing haemodynamic relevance of coronary artery stenosis; yet, the relationship of FFR to changes in myocardial oxygenation during vasodilator stress and thus to an objective marker for ischaemia on the tissue level is not well understood. METHODS AND RESULTS We prospectively recruited 64 patients with suspected/known coronary artery disease undergoing invasive angiography. The FFR was performed in intermediate coronary artery stenosis. OS-CMR images were acquired using a T2*-sensitive sequence before and after adenosine-induced vasodilation, with myocardial segments matched to angiography. Very strict image quality criteria were defined to ensure the validity of results. The FFR was performed in 37 patients. Because of the strict image quality criteria, 41% of segments had to be excluded, leaving 29/64 patients for the blinded OS-CMR analysis. Coronary territories with an associated FFR of <0.80 showed a lack of increase in myocardial oxygenation [mean signal intensity (ΔSI) -0.49%; 95% confidence interval (CI) -3.78 to 2.78 vs. +7.30%; 95% CI 4.08 to 10.64; P < 0.001]. An FFR of <0.54 best predicted a complete lack of a vasodilator-induced oxygenation increase (sensitivity 71% and specificity 75%). An OS-CMR ΔSI <4.78% identified an FFR of <0.8 with a sensitivity of 86% and specificity of 92%. CONCLUSION An FFR of <0.80 is associated with a lack of an adenosine-inducible increase in oxygenation of the dependent coronary territory, while a complete lack of such an increase was best predicted by an FFR of <0.54. Further studies are warranted to identify clinically meaningful cut-off values for FFR measurements and to assess the utility of OS-CMR as an alternative clinical tool for assessing the functional relevance of coronary artery stenosis.

Impact of hyperventilation and apnea on myocardial oxygenation in patients with obstructive sleep apnea – An oxygenation-sensitive CMR study

BACKGROUND Oxygenation-sensitive cardiovascular magnetic resonance imaging (OS-CMR) is an emerging technique that can monitor changes in myocardial oxygenation in vivo. Obstructive sleep apnea syndrome (OSAS) is associated with endothelial and microcirculatory dysfunction and increased cardiovascular morbidity and mortality. Little is known about myocardial responses to apnea in patients with OSAS. We hypothesized that the coronary vascular response to hyperventilation and long breath-hold is diminished in patients with OSAS when compared to healthy volunteers. METHODS Twenty-nine OSAS patients and 36 healthy volunteers were prospectively enrolled. All CMR scans were performed on a clinical 3T system. Participants performed a breathing maneuver with 60s of hyperventilation followed by a maximal breath-hold. During the breath-hold, OS-CMR images were continuously acquired and signal intensity changes were measured by a blinded reader. RESULTS Patients with OSAS were older than healthy volunteers (p<0.01) and presented more co-morbidities; 66% were currently treated with nocturnal positive airway pressure. Compared to healthy participants, the expected increase of myocardial oxygenation during the first 15s of the breath-hold was significantly lower in patients with OSAS (2.6±8.3% vs. 6.7±5.6%; p<0.05), and remained reduced at all time points during the breath-hold. Importantly this result was mainly driven by patients under continuous positive airway pressure (CPAP), suggesting that CPAP might have a greater impact on increase of myocardial oxygenation rather than OSAS itself. CONCLUSIONS The myocardial vascular response to combined breathing maneuvers of hyperventilation followed by voluntary apnea is blunted in patients with obstructive sleep apnea. Clinical studies should now further define the clinical role of oxygenation-sensitive CMR in patients with respiratory disorders.

Breathing Maneuvers as a Vasoactive Stimulus for Detecting Inducible Myocardial Ischemia – An Experimental Cardiovascular Magnetic Resonance Study

Background Breathing maneuvers can elicit a similar vascular response as vasodilatory agents like adenosine; yet, their potential diagnostic utility in the presence of coronary artery stenosis is unknown. The objective of the study is to investigate if breathing maneuvers can non-invasively detect inducible ischemia in an experimental animal model when the myocardium is imaged with oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR). Methods and Findings In 11 anesthetised swine with experimentally induced significant stenosis (fractional flow reserve <0.75) of the left anterior descending coronary artery (LAD) and 9 control animals, OS-CMR at 3T was performed during two different breathing maneuvers, a long breath-hold; and a combined maneuver of 60s of hyperventilation followed by a long breath-hold. The resulting change of myocardial oxygenation was compared to the invasive measurements of coronary blood flow, blood gases, and oxygen extraction. In control animals, all breathing maneuvers could significantly alter coronary blood flow as hyperventilation decreased coronary blood flow by 34±23%. A long breath-hold alone led to an increase of 97±88%, while the increase was 346±327% (p<0.001), when the long breath-hold was performed after hyperventilation. In stenosis animals, the coronary blood flow response was attenuated after both hyperventilation and the following breath-hold. This was matched by the observed oxygenation response as breath-holds following hyperventilation consistently yielded a significant difference in the signal of the MRI images between the perfusion territory of the stenosis LAD and remote myocardium. There was no difference between the coronary territories during the other breathing maneuvers or in the control group at any point. Conclusion In an experimental animal model, the response to a combined breathing maneuver of hyperventilation with subsequent breath-holding is blunted in myocardium subject to significant coronary artery stenosis. This maneuver may allow for detecting severe coronary artery stenosis and have a significant clinical potential as a non-pharmacological method for diagnostic testing in patients with suspected coronary artery disease.

Evidence for Acute Myocardial and Skeletal Muscle Injury after Serial Transthoracic Shocks in Healthy Swine

Background Previous serological studies have shown controversial results whether defibrillation or cardioversion can cause myocardial injury. Cardiovascular Magnetic Resonance (CMR) can be used to detect myocardial edema, hyperemia and capillary leak as features of acute myocardial injury. The aim of this study was to assess for myocardial and skeletal muscle injury in swine following transthoracic shocks. Methods Seventeen anaesthetized swine were examined, with 11 undergoing five synchronized transthoracic shocks (200J). Myocardial and skeletal muscle injury were assessed at baseline and up to 5h post-shock employing T1 mapping, T2 mapping, early and late gadolinium enhancement. Serologic markers (cFABP, TnI, CK, and CK-MB) and myocardial tissue were assessed by standard histology methods. Results In myocardial regions within the shock path, T1 and T2 were significantly increased compared to remote myocardium in the same animals. The early gadolinium enhancement ratio between the left-ventricular myocardium and the right pectoral muscle was also increased compared to control animals. After the shocks cFABP and CK were significantly elevated. After shock application, the regions identified as abnormal by CMR showed significantly increased interstitial and myocardial cell areas in histological analysis. This increased cell area suggests significant cellular and interstitial edema. Conclusion Our pilot study data indicate that serial defibrillator shocks lead to acute skeletal muscle and myocardial injury. CMR is a useful tool to detect and localize myocardial and skeletal muscle injury early after transthoracic shocks in vivo. In the future the technique could potentially be used as an additional tool for quality control such as verifying insufficient local shock application in non-responders after cardioversion or to develop safer shock forms.

Non-invasive monitoring of blood gas-induced changes of myocardial oxygenation using oxygen-sensitive CMR

Summary BOLD-CMR was used to assess changes in myocardial oxygenation after volunteers performed controlled hyperventilation or breath holding. Signal intensity after hyperventilation decreased whereas an increase occurred after a breath hold demonstrating that controlled breathing techniques could alter myocardial oxygenation and be identified by BOLD-CMR in healthy volunteers. Background Systemic changes of blood gases (CO2 ,O 2) affect haemoglobin (Hb) saturation. Blood Oxygen Level-Dependent (BOLD-) CMR can be used to monitor changes of myocardial oxygenation. We hypothesized that oxygensensitive CMR detects changes in myocardial tissue oxygenation induced by hyperventilation and apnea. Methods A group of 7 healthy volunteers were instructed to hyperventilate for 1 and 2 minutes followed by a long free breath hold. A second group of 5 aquatic athletes performed a 60s breath hold and a free maximal breath hold. BOLD-sensitive SSFP cines were acquired during breath holds as well as before and after hyperventilation. Changes in signal intensity over the procedures were expressed as % change of the baseline. Capillary blood gases were measured prior to and after the procedures. Results Voluntary breath holds of athletes were significantly longer (105±38s) than those of other volunteers (38 ±12s). Breath holds lead to a significant increase in signal intensity (*p<0.001), correlated with the length of breath hold (R=0.566, *p=0.018). Capillary pCO2 did not change during breath holds, while pO2 increased during shorter breath holds of 38s (+8.8 mmHg, *p=0.03) and decreased in long breath holds of 105s (-14.5mmHg, *p=0.03). On the other hand, hyperventilation resulted in a significant decrease of myocardial signal intensity, associated with a decrease of capillary pCO2 of 5.9 mmHg during 1 min of hyperventilation (*p<0.001) and 8.7 mmHg during a 2 min hyperventilation period (*p<0.001). Capillary pO2 was not altered by hyperventilation. Conclusions Our results demonstrate that BOLD-CMR can identify changes in myocardial oxygenation induced by controlled breathing maneuvers.

Functional significance of Blood Oxygen Level Dependent (BOLD) imaging in patients with coronary artery disease - a validation study using fractional flow reserve

Background/purpose Blood oxygen level-dependent (BOLD) cardiac MRI (CMR) uses the signal generated by endogenous hemoglobin in the blood supply to directly measure tissue oxygenation. Therefore it may be useful as a non-contrast enhanced, non-invasive method to detect the presence of myocardial ischemia in patients suspected of having coronary artery disease (CAD). The aim of this study was to validate whether BOLDsensitive CMR images can detect and quantify alterations in myocardial oxygen levels in patients with CAD, in comparison to the gold standard of fractional flow reserve (FFR). Methods Oxygen-sensitive BOLD CMR scans were performed in patients who were scheduled for clinically-indicated coronary angiography. BOLD images were captured during rest and adenosine-induced coronary hyperemia. The mean BOLD signal intensity (SI) percent changes were calculated between rest and hyperemia in the subendocardial myocardium at basal, mid, and apical regions. Segmental ΔSI% in the corresponding coronary territory was defined as ischemic (using a cut-off of <0.80) or non-ischemic by FFR. The BOLD segment with the lowest ΔSI% in the territory subtended by the FFR measurements was selected for statistical analysis. Bland-Altman analysis was used to assess the level of agreement between all segments analyzed by two blinded readers. Results Twenty-eight patients totaling 147 myocardial segments were available for analysis. 73 segments were excluded, with 66% of these being apical. The remaining 74 segments equated to 22 patients (60 +/- 9y, 19 males), eight of these had a normal FFR (≥ 0.80) and 14 had FFR values <0.80. Mean BOLD SI percent change was significantly less in patients with abnormal FFR values (-4.62 +/- 2.28% SEM), in comparison to patients with normal FFR values (8.54 +/- 3.08 % SEM); p=0.003. (See Figure 1 and 2). The Bland-Altman analysis indicated that the 95% limits of agreement between the two readers ranged from -23.6% to 27.8% (Figure 3).

Use of left ventricle blood pool oxygenation-sensitive signal intensity as a measure of arterial hemoglobin saturation

Background Oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR) relies on the attenuating effects of deoxyhemoglobin as an intrinsic contrast. When using OS-CMR to assess myocardial oxygenation, failing to account for effects on myocardial oxygen-sensitive signal intensity (OS-SI) due to arterial hemoglobin desaturation could confound results attributed to changes in perfusion and tissue metabolism. In particular, this can be relevant when using breath-holds as a vasodilating mechanism. Using an animal model we first assessed if arterial saturation can be non-invasively measured using the blood pool signal (SI) in OS-CMR images, and secondly if this effect is relevant for human studies. Methods In eight anaesthetized healthy swine, cannulas were placed in the femoral artery for blood sampling. Arterial and venous blood samples were taken from a human cohort of 36 healthy humans and 29 obstructive sleep apnea syndrome (OSAS) patients. All subjects performed a breathing maneuver of 60s hyperventilation followed by a long end-expiration breath-hold. In humans, the breath-hold duration was voluntary and analyzed for 30s, and in animals, manual ventilation performed and paused for 90s. OS-CMR images were acquired continuously throughout the breath-hold in a mid-slice short-axis slice with a bSSFP sequence (FA=35°, TR=3.4 ms) at 3T. SI values were captured in the left ventricle blood pool at end systole and expressed as a change over the breath-hold.