Kady Fischer

Impact of Intermittent Apnea on Myocardial Tissue Oxygenation—A Study Using Oxygenation-Sensitive Cardiovascular Magnetic Resonance

Background Carbon dioxide (CO2) is a recognized vasodilator of myocardial blood vessels that leads to changes in myocardial oxygenation through the recruitment of the coronary flow reserve. Yet, it is unknown whether changes of carbon dioxide induced by breathing maneuvers can be used to modify coronary blood flow and thus myocardial oxygenation. Oxygenation-sensitive cardiovascular magnetic resonance (CMR) using the blood oxygen level-dependent (BOLD) effect allows for non-invasive monitoring of changes of myocardial tissue oxygenation. We hypothesized that mild hypercapnia induced by long breath-holds leads to changes in myocardial oxygenation that can be detected by oxygenation-sensitive CMR. Methods and Results In nine anaesthetized and ventilated pigs, 60s breath-holds were induced. Left ventricular myocardial and blood pool oxygenation changes, as monitored by oxygenation-sensitive CMR using a T2*-weighted steady-state-free-precession (SSFP) sequence at 1.5T, were compared to changes of blood gas levels obtained immediately prior to and after the breath-hold. Long breath-holds resulted in an increase of paCO2, accompanied by a decrease of paO2 and pH. There was a significant decrease of blood pressure, while heart rate did not change. A decrease in the left ventricular blood pool oxygenation was observed, which was similar to drop in SaO2. Oxygenation in the myocardial tissue however, was maintained throughout the period. Changes in myocardial oxygenation were strongly correlated with the change in paCO2 during the breath-hold (r = 0.90, p = 0.010). Conclusion Despite a drop in blood oxygen levels, myocardial oxygenation is maintained throughout long breath-holds and is linearly correlated with the parallel increase of arterial CO2, a known coronary vasodilator. Breathing maneuvers in combination with oxygenation-sensitive CMR may be useful as a diagnostic test for coronary artery function.

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.

Myocardial oxygenation is maintained during hypoxia when combined with apnea – a cardiovascular MR study

Oxygenation‐sensitive (OS) cardiovascular magnetic resonance (CMR) is used to noninvasively measure myocardial oxygenation changes during pharmacologic vasodilation. The use of breathing maneuvers with OS CMR for diagnostic purposes has been recently proposed based on the vasodilatory effect of Co2, which can be enhanced by the additive effect of mild hypoxia. This study seeks to investigate this synergistic concept on coronary arteriolar resistance with OS CMR. In nine anesthetized swine, normoxemic and mild hypoxemic arterial partial pressure of oxygen (Pao2) levels (100 and 80 mmHg) were targeted with three arterial partial pressure of carbon dioxide (Paco2) levels of 30, 40, and 50 mmHg. During a 60‐sec apnea from the set baselines, OS T2*‐weighted gradient echo steady‐state free precession (SSFP) cine series were obtained in a clinical 1.5T magnetic resonance imaging (MRI) system. Arterial blood gases were acquired prior to and after apnea. Changes in global myocardial signal intensity (SI) were measured. Although a greater drop in arterial oxygen saturation (SaO2) was observed in the hypoxemic baselines, myocardial SI increased or was maintained during apnea in all levels (n = 6). An observed decrease in left ventricular blood pool SI was correlated with the drop in SaO2. Corrected for the arterial desaturation, the calculated SI increase attributable to the increase in myocardial blood flow was greater in the hypoxemic levels. Both the changes in Paco2 and Pao2 were correlated with myocardial SI changes at normoxemia, yet not at hypoxemic levels. Using OS CMR, we found evidence that myocardial oxygenation is preserved during hypoxia when combined with Co2‐increasing maneuvers, indicating synergistic effects of hypoxemia and hypercapnia on myocardial blood flow.

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.

Breathing maneuvers as a coronary vasodilator for myocardial perfusion imaging

A combined breathing maneuver of hyperventilation, followed by a long voluntary breathhold leads to coronary vasodilation. We investigated the impact of breathing maneuvers on MR first‐pass cardiac perfusion imaging and its potential clinical utility.

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.