Improved accuracy and precision with three-parameter simultaneous myocardial T1 and T2 mapping using multiparametric SASHA.

PURPOSE: To develop and validate a three-parameter model for improved precision multiparametric SAturation-recovery single-SHot Acquisition (mSASHA) cardiac T1 and T2 mapping with high accuracy in a single breath-hold. METHODS: The mSASHA acquisition consists of nine images of variable saturation recovery and T2 preparation in 11 heartbeats with T1 and T2 values calculated using a three-parameter model. It was validated in simulations and phantoms at 3 T with comparison to a four-parameter joint T1 -T2 technique. The mSASHA acquisition was compared with MOLLI, SASHA, and T2 -prepared balanced SSFP in 10 volunteers. RESULTS: The mSASHA technique had high accuracy in phantoms compared to spin echo, with -0.2 ± 0.3% T1 error and -2.4 ± 1.3% T2 error. The mSASHA coefficient of variation in phantoms for T1 was similar to MOLLI (0.7 ± 0.2% for both) and T2 -prepared balanced SSFP for T2 (1.3 ± 0.7% vs 1.4 ± 0.3%, adjusted p > .05 for both). In simulations, three-parameter mSASHA had higher precision than four-parameter joint T1 -T2 for both T1 and T2 (46% and 11% reductions in T1 and T2 interquartile range for native myocardium). In vivo myocardial mSASHA T1 was similar to SASHA (1523 ± 18 ms vs 1520 ± 18 ms) with similar coefficient of variation to both MOLLI and SASHA (3.3 ± 0.6% vs 3.1 ± 0.6% and 3.3 ± 0.5% respectively, adjusted p > .05 for all). Myocardial mSASHA T2 was 37.1 ± 1.1 ms with similar precision to T2 -prepared balanced SSFP (6.7 ± 1.7% vs 6.0 ± 1.6%, adjusted p > .05). CONCLUSION: Three-parameter mSASHA provides high-accuracy cardiac T1 and T2 quantification in a single breath-hold with similar precision to MOLLI and T2 -prepared balanced SSFP. Further study is required to both establish normative values and demonstrate clinical utility in patient populations.

Acellular bioscaffolds redirect cardiac fibroblasts and promote functional tissue repair in rodents and humans with myocardial injury.

Coronary heart disease is a leading cause of death. Tissue remodeling and fibrosis results in cardiac pump dysfunction and ischemic heart failure. Cardiac fibroblasts may rebuild damaged tissues when prompted by suitable environmental cues. Here, we use acellular biologic extracellular matrix scaffolds (bioscaffolds) to stimulate pathways of muscle repair and restore tissue function. We show that acellular bioscaffolds with bioinductive properties can redirect cardiac fibroblasts to rebuild microvascular networks and avoid tissue fibrosis. Specifically, when human cardiac fibroblasts are combined with bioactive scaffolds, gene expression is upregulated and paracrine mediators are released that promote vasculogenesis and prevent scarring. We assess these properties in rodents with myocardial infarction and observe bioscaffolds to redirect fibroblasts, reduce tissue fibrosis and prevent maladaptive structural remodeling. Our preclinical data confirms that acellular bioscaffold therapy provides an appropriate microenvironment to stimulate pathways of functional repair. We translate our observations to patients with coronary heart disease by conducting a first-in-human observational cohort study. We show that bioscaffold therapy is associated with improved perfusion of infarcted myocardium, reduced myocardial scar burden, and reverse structural remodeling. We establish that clinical use of acellular bioscaffolds is feasible and offers a new frontier to enhance surgical revascularization of ischemic heart muscle.

Hyperventilation-induced heart rate response as a potential marker for cardiovascular disease.

An increase of heart rate to physical or mental stress reflects the ability of the autonomous nervous system and the heart to respond adequately. Hyperventilation is a user-controlled breathing maneuver that has a significant impact on coronary function and hemodynamics. Thus, we aimed to investigate if the heart rate response to hyperventilation (HRRHV) can provide clinically useful information. A pooled analysis of the HRRHV after 60 s of hyperventilation was conducted in 282 participants including healthy controls; patients with heart failure (HF); coronary artery disease (CAD); a combination of both; or patients suspected of CAD but with a normal angiogram. Hyperventilation significantly increased heart rate in all groups, although healthy controls aged 55 years and older (15 ± 9 bpm) had a larger HRRHV than each of the disease groups (HF: 6 ± 6, CAD: 8 ± 8, CAD+/HF+: 6 ± 4, and CAD-/HF-: 8 ± 6 bpm, p < 0.001). No significant differences were found between disease groups. The HRRHV may serve as an easily measurable additional marker of cardiovascular health. Future studies should test its diagnostic potential as a simple, inexpensive pre-screening test to improve patient selection for other diagnostic exams.

Epicardial infarct repair with bioinductive extracellular matrix promotes vasculogenesis and myocardial recovery.

BACKGROUND: Infarcted myocardium can remodel after successful reperfusion, resulting in left ventricular dilation and heart failure. Epicardial infarct repair (EIR) using a bioinductive extracellular matrix (ECM) biomaterial is a novel surgical approach to promote endogenous myocardial repair and functional recovery after myocardial infarction. Using a pre-clinical porcine model of coronary ischemia-reperfusion, we assessed the effects of EIR on regional functional recovery, safety, and possible mechanisms of benefit. METHODS: An ECM biomaterial (CorMatrix ECM) was applied to the epicardium after 75 minutes of coronary ischemia in a porcine model. Following ischemia-reperfusion injury, animals were randomly assigned in 2:1 fashion to EIR (n = 8) or sham treatment (n = 4). Serial cardiac magnetic resonance imaging was performed on normal (n = 4) and study animals at baseline (1 week) and 6 weeks after treatment. Myocardial function and tissue characteristics were assessed. RESULTS: Functional myocardial recovery was significantly increased by EIR compared with sham treatment (change in regional myocardial contraction at 6 weeks, 28.6 ± 14.0% vs 4.2 ± 13.5% wall thickening, p < 0.05). Animals receiving EIR had reduced adhesions compared with animals receiving sham treatment (1.44 ± 0.51 vs 3.08 ± 0.89, p < 0.05). Myocardial fibrosis was not increased, and EIR did not cause myocardial constriction, as left ventricular compliance by passive pressure distention at matched volumes was similar between groups (13.9 ± 4.0 mm Hg in EIR group vs 16.0 ± 5.2 mm Hg in sham group, p = 0.61). Animals receiving EIR showed evidence of vasculogenesis in the region of functional recovery. CONCLUSIONS: In addition to the beneficial effects of successful reperfusion, EIR using a bioinductive ECM enhances myocardial repair and functional recovery. Clinical translation of EIR early after myocardial infarction as an adjunct to surgical revascularization may be warranted in the future.

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.

Saturation recovery single-shot acquisition (SASHA) for myocardial T(1) mapping.

PURPOSE: To validate a new saturation recovery single-shot acquisition (SASHA) pulse sequence for T1 mapping and to compare SASHA T1 values in heart failure patients and healthy controls. THEORY: The SASHA sequence consists of 10 electrocardiogram-triggered single-shot balanced steady-state free precession images in a breath-hold. The first image is acquired without magnetization preparation and the remaining nine images follow saturation pulses with variable saturation recovery times. METHODS: SASHA was validated through Bloch equation simulations, Monte Carlo simulations, and phantom experiments. Pre- and postcontrast myocardial and blood T1 values were measured in 29 healthy volunteers and 7 patients with heart failure. RESULTS: SASHA T1 values had excellent agreement (bias, 5 ± 5 ms) with spin echo experiments in phantoms with a wide range of physiologic T1 and T2 values and its accuracy was independent of flip angle, absolute T1 , T2 , and heart rate. The average baseline myocardial T1 in heart failure patients was higher than in healthy controls (1200 ± 32 vs. 1170 ± 9 ms, P < 0.05) at 1.5T, as was the calculated blood-tissue partition coefficient, λ, (0.42 ± 0.04 vs. 0.38 ± 0.02, P < 0.05), consistent with diffuse myocardial fibrosis. CONCLUSIONS: The SASHA sequence is a simple and fast approach to in vivo T1 mapping with good accuracy in simulations and phantom experiments.

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.

Assessment of acute myocarditis by cardiovascular MR: diagnostic performance of shortened protocols.

The recommended cardiovascular magnetic resonance (CMR) diagnostic criteria for active myocarditis ("Lake Louise Criteria") are based on edema-sensitive (T2-weighted) imaging and two different contrast-enhanced techniques, the early gadolinium enhancement ratio (EGEr) and late gadolinium enhancement (LGE). Because fast spin echo sequences used for determining the EGEr and edema-sensitive T2-weighted sequences have inconsistent image quality, these components are often skipped in institutional standard protocols. We aimed to compare the diagnostic performance of the Lake Louise Criteria with and without T2-weighted or early gadolinium-enhanced CMR imaging in a clinical setting. We investigated 35 patients with suspected acute myocarditis (27 males; Age 39.8 ± 16.6) and 10 healthy controls (5 males; age 33.8 ± 10.4). CMR sequences investigated included an edema-sensitive short-T1 triple inversion recovery, T1-weighted turbo spin echo imaging before and within 4 min after gadolinium injection (EGEr), and a phase sensitive inversion-recovery gradient echo sequence 5-10 min after gadolinium injection (LGE). Quantitative and qualitative image analyses, respectively, were performed for EGEr and areas with increased signal in LGE and edema-sensitive images. EGEr, T2, and LGE burden were significantly higher in patients than in controls (EGEr: 5.8 ± 3.0 vs. 2.5 ± 1.7; p = 0.002, T2: 24 vs. 0; p < 0.001, LGE: 27 vs. 4; p < 0.05). The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were as follows: EGEr: 66, 90, 96, 43, and 72%; T2: 69, 100, 100, 53, and 76%; LGE: 77, 60, 87, 43 and 73%; T2 and/or LGE: 91, 60, 89, 67, 84% Lake Louise Criteria, "two out of three": 80, 90, 96, 53, and 82%. The sensitivity of "T2 and/or LGE" was significantly higher than the Lake Louise Criteria (p < 0.05), while the overall diagnostic accuracy was not statistically different. The overall diagnostic accuracy "T2 and/or LGE" was significantly better than that of LGE alone. The positive likelihood ratio was higher for the Lake Louise Criteria (7.7) than for EGE alone (6.3), T2 and/or LGE (2.3) or LGE alone (1.9). In patients with clinical evidence for relevant active myocarditis, skipping T2-weighted imaging or early GD enhancement is associated with a significantly lower positive likelihood ratio, while the removal of Early Gd Enhancement imaging does not change diagnostic overall accuracy, while reducing sensitivity. Thus, in patients where a high positive likelihood ratio is needed, the full Lake Louise Criteria including Early Gd enhancement and edema-sensitive T2-weighted imaging should be used until alternative approaches are developed.

Impact of intermittent apnea on myocardial tissue oxygenation--a study using oxygenation-sensitive cardiovascular magnetic resonance.

BACKGROUND: Carbon dioxide (CO(2)) 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 paCO(2), accompanied by a decrease of paO(2) 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 SaO(2). Oxygenation in the myocardial tissue however, was maintained throughout the period. Changes in myocardial oxygenation were strongly correlated with the change in paCO(2) 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 CO(2), a known coronary vasodilator. Breathing maneuvers in combination with oxygenation-sensitive CMR may be useful as a diagnostic test for coronary artery function.

Oxygenation-sensitive CMR for assessing vasodilator-induced changes of myocardial oxygenation.

BACKGROUND: As myocardial oxygenation may serve as a marker for ischemia and microvascular dysfunction, it could be clinically useful to have a non-invasive measure of changes in myocardial oxygenation. However, the impact of induced blood flow changes on oxygenation is not well understood. We used oxygenation-sensitive CMR to assess the relations between myocardial oxygenation and coronary sinus blood oxygen saturation (SvO2) and coronary blood flow in a dog model in which hyperemia was induced by intracoronary administration of vasodilators. RESULTS: During administration of acetylcholine and adenosine, CMR signal intensity correlated linearly with simultaneously measured SvO2 (r2 = 0.74, P < 0.001). Both SvO2 and CMR signal intensity were exponentially related to coronary blood flow, with SvO2 approaching 87%. CONCLUSIONS: Myocardial oxygenation as assessed with oxygenation-sensitive CMR imaging is linearly related to SvO2 and is exponentially related to vasodilator-induced increases of blood flow. Oxygenation-sensitive CMR may be useful to assess ischemia and microvascular function in patients. Its clinical utility should be evaluated.

Single-shot steady-state free precession can detect myocardial edema in patients: a feasibility study.

PURPOSE: To demonstrate the ability of single-shot, T(2)/T(1) weighted steady-state free precession (SSFP) to detect myocardial edema in patients with an acute myocardial infarction. MATERIALS AND METHODS: This study was performed in a series of patients (n = 10) referred for the assessment of acute myocardial infarcts (AMI). Localizers were used to obtain true short axis views of the left ventricle (LV). These views were used to plan and obtain T(2)-weighted STIR (short TI inversion recovery) images of the LV. These slices were then acquired using single-shot dark blood-prepared SSFP with a large (31) number of dummy pulses. Lastly, Contrast agent was injected, and late enhancement (LE) images were acquired. Images were analyzed using a multi-segment model of the heart. SSFP images were compared with STIR images, with STIR images used as the standard of truth for the presence of edema. LE images were used to identify segments which were positive for microvascular obstruction. RESULTS: All techniques were successful in all patients. A total of 312 segments were analyzed. Excluding segments positive for microvascular obstruction, SSFP had a sensitivity/specificity of 80%/89%. Including segments positive for microvascular obstruction, sensitivity/specificity was 71%/88%. On a patient-based analysis, no AMI was missed using SSFP (sensitivity = 100%). CONCLUSION: Using single-shot SSFP to detect myocardial edema in patients with AMI is feasible with a moderate sensitivity and high specificity.

Wave intensity analysis and the development of the reservoir-wave approach.

The parameters of wave intensity analysis are calculated from incremental changes in pressure and velocity. While it is clear that forward- and backward-traveling waves induce incremental changes in pressure, not all incremental changes in pressure are due to waves; changes in pressure may also be due to changes in the volume of a compliant structure. When the left ventricular ejects blood rapidly into the aorta, aortic pressure increases, in part, because of the increase in aortic volume: aortic inflow is momentarily greater than aortic outflow. Therefore, to properly quantify the effects of forward or backward waves on arterial pressure and velocity (flow), the component of the incremental change in arterial pressure that is due only to this increase in arterial volume--and not, fundamentally, due to waves--first must be excluded. This component is the pressure generated by the filling and emptying of the reservoir, Otto Frank's Windkessel.

Wave intensity analysis of left ventricular filling: application of windkessel theory.

We extend our recently published windkessel-wave interpretation of vascular function to the wave intensity analysis (WIA) of left ventricular (LV) filling dynamics by separating the pressure changes due to the windkessel from those due to traveling waves. With the use of LV compliance, the change in pressure due solely to LV volume changes (windkessel pressure) can be isolated. Inasmuch as the pressure measured in the cardiovascular system is the sum of its windkessel and wave components (excess pressure), it can be substituted into WIA, yielding the isolated wave effects on LV filling. Our study of six open-chest dogs demonstrated that once the windkessel effects are removed from WIA, the energy of diastolic suction is 2.6 times greater than we previously calculated. Volume-related changes in pressure (i.e., the windkessel or reservoir effect) must be considered first when wave motion is analyzed.

Wave intensity analysis of left atrial mechanics and energetics in anesthetized dogs.

The left atrium (LA) acts as a booster pump during late diastole, generating the Doppler transmitral A wave and contributing incrementally to left ventricular (LV) filling. However, after volume loading and in certain disease states, LA contraction fills the LV less effectively, and retrograde flow (i.e., the Doppler Ar wave) into the pulmonary veins increases. The purpose of this study was to provide an energetic analysis of LA contraction to clarify the mechanisms responsible for changes in forward and backward flow. Wave intensity analysis was performed at the mitral valve and a pulmonary vein orifice. As operative LV stiffness increased with progressive volume loading, the reflection coefficient (i.e., energy of reflected wave/energy of incident wave) also increased. This reflected wave decelerated the forward movement of blood through the mitral valve and was transmitted through the LA, accelerating retrograde blood flow in the pulmonary veins. Although total LA work increased with volume loading, the forward hydraulic work decreased and backward hydraulic work increased. Thus wave reflection due to increased LV stiffness accounts for the decrease in the A wave and the increase in the Ar wave measured by Doppler.

Systemic venous circulation. Waves propagating on a windkessel: relation of arterial and venous windkessels to systemic vascular resistance.

Compared with arterial hemodynamics, there has been relatively little study of venous hemodynamics. We propose that the venous system behaves just like the arterial system: waves propagate on a time-varying reservoir, the windkessel, which functions as the reverse of the arterial windkessel. During later diastole, pressure increases exponentially to approach an asymptotic value as inflow continues in the absence of outflow. Our study in eight open-chest dogs showed that windkessel-related arterial resistance was approximately 62% of total systemic vascular resistance, whereas windkessel-related venous resistance was only approximately 7%. Total venous compliance was found to be 21 times larger than arterial compliance (n = 3). Inferior vena caval compliance (0.32 +/- 0.015 ml x mmHg(-1) x kg(-1); mean +/- SE) was approximately 14 times the aortic compliance (0.023 +/- 0.002 ml x mmHg(-1) x kg(-1); n = 8). Despite greater venous compliance, the variation in venous windkessel volume (i.e., compliance x windkessel pulse pressure; 7.8 +/- 1.1 ml) was only approximately 32% of the variation in aortic windkessel volume (24.3 +/- 2.9 ml) because of the larger arterial pressure variation. In addition, and contrary to previous understanding, waves generated by the right heart propagated upstream as far as the femoral vein, but excellent proportionality between the excess pressure and venous outflow suggests that no reflected waves returned to the right atrium. Thus the venous windkessel model not only successfully accounts for variations in the venous pressure and flow waveforms but also, in combination with the arterial windkessel, provides a coherent view of the systemic circulation.