Rohan S. Wijesurendra

Adenosine Stress and Rest T1 Mapping Can Differentiate Between Ischemic, Infarcted, Remote, and Normal Myocardium Without the Need for Gadolinium Contrast Agents

Objectives The aim of this study was to evaluate the potential of T1 mapping at rest and during adenosine stress as a novel method for ischemia detection without the use of gadolinium contrast. Background In chronic coronary artery disease (CAD), accurate detection of ischemia is important because targeted revascularization improves clinical outcomes. Myocardial blood volume (MBV) may be a more comprehensive marker of ischemia than myocardial blood flow. T1 mapping using cardiac magnetic resonance (CMR) is highly sensitive to changes in myocardial water content, including MBV. We propose that T1 mapping at rest and during adenosine vasodilatory stress can detect MBV changes in normal and diseased myocardium in CAD. Methods Twenty normal controls (10 at 1.5-T; 10 at 3.0-T) and 10 CAD patients (1.5-T) underwent conventional CMR to assess for left ventricular function (cine), infarction (late gadolinium enhancement [LGE]) and ischemia (myocardial perfusion reserve index [MPRI] on first-pass perfusion imaging during adenosine stress). These were compared to novel pre-contrast stress/rest T1 mapping using the Shortened Modified Look-Locker Inversion recovery technique, which is heart rate independent. T1 values were derived for normal myocardium in controls and for infarcted, ischemic, and remote myocardium in CAD patients. Results Normal myocardium in controls (normal wall motion, MPRI, no LGE) showed normal resting T1 (954 ± 19 ms at 1.5-T; 1,189 ± 34 ms at 3.0-T) and significant positive T1 reactivity during adenosine stress compared to baseline (6.2 ± 0.5% at 1.5-T; 6.3 ± 1.1% at 3.0-T; all p < 0.0001). Infarcted myocardium showed the highest resting T1 of all tissue classes (1,442 ± 84 ms), without significant T1 reactivity (0.2 ± 1.5%). Ischemic myocardium showed elevated resting T1 compared to normal (987 ± 17 ms; p < 0.001) without significant T1 reactivity (0.2 ± 0.8%). Remote myocardium, although having comparable resting T1 to normal (955 ± 17 ms; p = 0.92), showed blunted T1 reactivity (3.9 ± 0.6%; p < 0.001). Conclusions T1 mapping at rest and during adenosine stress can differentiate between normal, infarcted, ischemic, and remote myocardium with distinctive T1 profiles. Stress/rest T1 mapping holds promise for ischemia detection without the need for gadolinium contrast.

Cardiac energetics, oxygenation, and perfusion during increased workload in patients with type 2 diabetes mellitus

Aims Patients with type 2 diabetes mellitus (T2DM) are known to have impaired resting myocardial energetics and impaired myocardial perfusion reserve, even in the absence of obstructive epicardial coronary artery disease (CAD). Whether or not the pre-existing energetic deficit is exacerbated by exercise, and whether the impaired myocardial perfusion causes deoxygenation and further energetic derangement during exercise stress, is uncertain. Methods and results Thirty-one T2DM patients, on oral antidiabetic therapies with a mean HBA1c of 7.4 ± 1.3%, and 17 matched controls underwent adenosine stress cardiovascular magnetic resonance for assessment of perfusion [myocardial perfusion reserve index (MPRI)] and oxygenation [blood-oxygen level-dependent (BOLD) signal intensity change (SIΔ)]. Cardiac phosphorus-MR spectroscopy was performed at rest and during leg exercise. Significant CAD (>50% coronary stenosis) was excluded in all patients by coronary computed tomographic angiography. Resting phosphocreatine to ATP (PCr/ATP) was reduced by 17% in patients (1.74 ± 0.26, P = 0.001), compared with controls (2.07 ± 0.35); during exercise, there was a further 12% reduction in PCr/ATP (P = 0.005) in T2DM patients, but no change in controls. Myocardial perfusion and oxygenation were decreased in T2DM (MPRI 1.61 ± 0.43 vs. 2.11 ± 0.68 in controls, P = 0.002; BOLD SIΔ 7.3 ± 7.8 vs. 17.1 ± 7.2% in controls, P < 0.001). Exercise PCr/ATP correlated with MPRI (r = 0.50, P = 0.001) and BOLD SIΔ (r = 0.32, P = 0.025), but there were no correlations between rest PCr/ATP and MPRI or BOLD SIΔ. Conclusion The pre-existing energetic deficit in diabetic cardiomyopathy is exacerbated by exercise; stress PCr/ATP correlates with impaired perfusion and oxygenation. Our findings suggest that, in diabetes, coronary microvascular dysfunction exacerbates derangement of cardiac energetics under conditions of increased workload.

Molecular imaging with optical coherence tomography using ligand-conjugated microparticles that detect activated endothelial cells: Rational design through target quantification

Objectives Optical coherence tomography (OCT) is a high resolution imaging technique used to assess superficial atherosclerotic plaque morphology. Utility of OCT may be enhanced by contrast agents targeting molecular mediators of inflammation. Methods and results Microparticles of iron oxide (MPIO; 1 and 4.5 μm diameter) in suspension were visualized and accurately quantified using a clinical optical coherence tomography system. Bound to PECAM-1 on a plane of cultured endothelial cells under static conditions, 1 μm MPIO were also readily detected by OCT. To design a molecular contrast probe that would bind activated endothelium under conditions of shear stress, we quantified the expression (basal vs. TNF-activated; molecules μm−2) of VCAM-1 (not detected vs. 16 ± 1); PECAM-1 (132 ± 6 vs. 198 ± 10) and E-selectin (not detected vs. 46 ± 0.6) using quantitative flow cytometry. We then compared the retention of antibody-conjugated MPIO targeting each of these molecules plus a combined VCAM-1 and E-selectin (E + V) probe across a range of physiologically relevant shear stresses. E + V MPIO were consistently retained with highest efficiency (P < 0.001) and at a density that provided conspicuous contrast effects on OCT pullback. Conclusion Microparticles of iron oxide were detectable using a clinical OCT system. Assessment of binding under flow conditions recommended an approach that targeted both E-selectin and VCAM-1. Bound to HUVEC under conditions of flow, targeted 1 μm E + V MPIO were readily identified on OCT pullback. Molecular imaging with OCT may be feasible in vivo using antibody targeted MPIO.

Lone Atrial Fibrillation Is Associated With Impaired Left Ventricular Energetics That Persists Despite Successful Catheter Ablation

Background: Lone atrial fibrillation (AF) may reflect a subclinical cardiomyopathy that persists after sinus rhythm (SR) restoration, providing a substrate for AF recurrence. To test this hypothesis, we investigated the effect of restoring SR by catheter ablation on left ventricular (LV) function and energetics in patients with AF but no significant comorbidities. Methods: Fifty-three patients with symptomatic paroxysmal or persistent AF and without significant valvular disease, uncontrolled hypertension, coronary artery disease, uncontrolled thyroid disease, systemic inflammatory disease, diabetes mellitus, or obstructive sleep apnea (ie, lone AF) undergoing ablation and 25 matched control subjects in SR were investigated. Magnetic resonance imaging quantified LV ejection fraction (LVEF), peak systolic circumferential strain (PSCS), and left atrial volumes and function, whereas phosphorus-31 magnetic resonance spectroscopy evaluated ventricular energetics (ratio of phosphocreatine to ATP). AF burden was determined before and after ablation by 7-day Holter monitoring; intermittent ECG event monitoring was also undertaken after ablation to investigate for asymptomatic AF recurrence. Results: Before ablation, both LV function and energetics were significantly impaired in patients compared with control subjects (LVEF, 61% [interquartile range (IQR), 52%–65%] versus 71% [IQR, 69%–73%], P<0.001; PSCS, –15% [IQR, –11 to –18%] versus −18% [IQR, –17% to –19%], P=0.002; ratio of phosphocreatine to ATP, 1.81±0.35 versus 2.05±0.29, P=0.004). As expected, patients also had dilated and impaired left atria compared with control subjects (all P<0.001). Early after ablation (1–4 days), LVEF and PSCS improved in patients recovering SR from AF (LVEF, 7.0±10%, P=0.005; PSCS, –3.5±4.3%, P=0.001) but were unchanged in those in SR during both assessments (both P=NS). At 6 to 9 months after ablation, AF burden reduced significantly (from 54% [IQR, 1.5%–100%] to 0% [IQR 0%–0.1%]; P<0.001). However, LVEF and PSCS did not improve further (both P=NS) and remained impaired compared with control subjects (P<0.001 and P=0.003, respectively). Similarly, there was no significant improvement in atrial function from before ablation (P=NS), and this remained lower than in control subjects (P<0.001). The ratio of phosphocreatine to ATP was unaffected by heart rhythm during assessment and AF burden before ablation (both P=NS). It was unchanged after ablation (P=0.57), remaining lower than in control subjects regardless of both recovery of SR and freedom from recurrent AF (P=0.006 and P=0.002, respectively). Conclusions: Patients with lone AF have impaired myocardial energetics and subtle LV dysfunction, which do not normalize after ablation. These findings suggest that AF may be the consequence (rather than the cause) of an occult cardiomyopathy, which persists despite a significant reduction in AF burden after ablation.

Atrial fibrillation: effects beyond the atrium?

Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is associated with significant morbidity, mostly secondary to heart failure and stroke, and an estimated two-fold increase in premature death. Efforts to increase our understanding of AF and its complications have focused on unravelling the mechanisms of electrical and structural remodelling of the atrial myocardium. Yet, it is increasingly recognized that AF is more than an atrial disease, being associated with systemic inflammation, endothelial dysfunction, and adverse effects on the structure and function of the left ventricular myocardium that may be prognostically important. Here, we review the molecular and in vivo evidence that underpins current knowledge regarding the effects of human or experimental AF on the ventricular myocardium. Potential mechanisms are explored including diffuse ventricular fibrosis, focal myocardial scarring, and impaired myocardial perfusion and perfusion reserve. The complex relationship between AF, systemic inflammation, as well as endothelial/microvascular dysfunction and the effects of AF on ventricular calcium handling and oxidative stress are also addressed. Finally, consideration is given to the clinical implications of these observations and concepts, with particular reference to rate vs. rhythm control.

CMR Native T1 Mapping Allows Differentiation of Reversible Versus Irreversible Myocardial Damage in ST-Segment-Elevation Myocardial Infarction: An OxAMI Study (Oxford Acute Myocardial Infarction).

Background— CMR T1 mapping is a quantitative imaging technique allowing the assessment of myocardial injury early after ST-segment–elevation myocardial infarction. We sought to investigate the ability of acute native T1 mapping to differentiate reversible and irreversible myocardial injury and its predictive value for left ventricular remodeling. Methods and Results— Sixty ST-segment–elevation myocardial infarction patients underwent acute and 6-month 3T CMR, including cine, T2-weighted (T2W) imaging, native shortened modified look-locker inversion recovery T1 mapping, rest first pass perfusion, and late gadolinium enhancement. T1 cutoff values for oedematous versus necrotic myocardium were identified as 1251 ms and 1400 ms, respectively, with prediction accuracy of 96.7% (95% confidence interval, 82.8% to 99.9%). Using the proposed threshold of 1400 ms, the volume of irreversibly damaged tissue was in good agreement with the 6-month late gadolinium enhancement volume (r=0.99) and correlated strongly with the log area under the curve troponin (r=0.80) and strongly with 6-month ejection fraction (r=−0.73). Acute T1 values were a strong predictor of 6-month wall thickening compared with late gadolinium enhancement. Conclusions— Acute native shortened modified look-locker inversion recovery T1 mapping differentiates reversible and irreversible myocardial injury, and it is a strong predictor of left ventricular remodeling in ST-segment–elevation myocardial infarction. A single CMR acquisition of native T1 mapping could potentially represent a fast, safe, and accurate method for early stratification of acute patients in need of more aggressive treatment. Further confirmatory studies will be needed.

Up-regulation of miR-31 in human atrial fibrillation begets the arrhythmia by depleting dystrophin and neuronal nitric oxide synthase

Atrial microRNA-31 up-regulation causes dystrophin and nNOS depletion, which in turn contributes to the electrical phenotype of atrial fibrillation. Rhythm remodeling traced to tiny RNA Atrial fibrillation (AF) is characterized by abnormal heart rhythms and can be caused by a variety of risk factors ranging from obesity to diabetes. Although treatments exist, AF is famously able to recur by “remodeling” the heart tissue electrically and structurally to maintain its unsteady beat. Reilly et al. have discovered a small noncoding RNA, miR-31, that is responsible for a string of signals that allow for such remodeling. An increase in miR-31 led to depletion of neuronal nitric oxide synthase (nNOS) and repression of dystrophin (which binds nNOS in muscle cells) in the fibrillating atrial myocardium of both humans and goats. These mechanistic findings were further explored in mice. Because up-regulation of miR-31 and the resulting loss of dystrophin and nNOS in AF are specific to the atrium, it may be possible to target interventions to this remodeling pathway, thus providing a safer therapeutic option for patients with AF than those that are currently available, including ablation and ion channel blockers. Atrial fibrillation (AF) is a growing public health burden, and its treatment remains a challenge. AF leads to electrical remodeling of the atria, which in turn promotes AF maintenance and resistance to treatment. Although remodeling has long been a therapeutic target in AF, its causes remain poorly understood. We show that atrial-specific up-regulation of microRNA-31 (miR-31) in goat and human AF depletes neuronal nitric oxide synthase (nNOS) by accelerating mRNA decay and alters nNOS subcellular localization by repressing dystrophin translation. By shortening action potential duration and abolishing rate-dependent adaptation of the action potential duration, miR-31 overexpression and/or disruption of nNOS signaling recapitulates features of AF-induced remodeling and significantly increases AF inducibility in mice in vivo. By contrast, silencing miR-31 in atrial myocytes from patients with AF restores dystrophin and nNOS and normalizes action potential duration and its rate dependency. These findings identify atrial-specific up-regulation of miR-31 in human AF as a key mechanism causing atrial dystrophin and nNOS depletion, which in turn contributes to the atrial phenotype begetting this arrhythmia. miR-31 may therefore represent a potential therapeutic target in AF.

Diagnosis of Microvascular Angina Using Cardiac Magnetic Resonance

Background In patients with angina and nonobstructive coronary artery disease (NOCAD), confirming symptoms due to coronary microvascular dysfunction (CMD) remains challenging. Cardiac magnetic resonance (CMR) assesses myocardial perfusion with high spatial resolution and is widely used for diagnosing obstructive coronary artery disease (CAD). Objectives The goal of this study was to validate CMR for diagnosing microvascular angina in patients with NOCAD, compared with patients with obstructive CAD and correlated to the index of microcirculatory resistance (IMR) during invasive coronary angiography. Methods Fifty patients with angina (65 ± 9 years of age) and 20 age-matched healthy control subjects underwent adenosine stress CMR (1.5- and 3-T) to assess left ventricular function, inducible ischemia (myocardial perfusion reserve index [MPRI]; myocardial blood flow [MBF]), and infarction (late gadolinium enhancement). During subsequent angiography within 7 days, 28 patients had obstructive CAD (fractional flow reserve [FFR] ≤0.8) and 22 patients had NOCAD (FFR >0.8) who underwent 3-vessel IMR measurements. Results In patients with NOCAD, myocardium with IMR <25 U had normal MPRI (1.9 ± 0.4 vs. controls 2.0 ± 0.3; p = 0.49); myocardium with IMR ≥25 U had significantly impaired MPRI, similar to ischemic myocardium downstream of obstructive CAD (1.2 ± 0.3 vs. 1.2 ± 0.4; p = 0.61). An MPRI of 1.4 accurately detected impaired perfusion related to CMD (IMR ≥25 U; FFR >0.8) (area under the curve: 0.90; specificity: 95%; sensitivity: 89%; p < 0.001). Impaired MPRI in patients with NOCAD was driven by impaired augmentation of MBF during stress, with normal resting MBF. Myocardium with FFR >0.8 and normal IMR (<25 U) still had blunted stress MBF, suggesting mild CMD, which was distinguishable from control subjects by using a stress MBF threshold of 2.3 ml/min/g with 100% positive predictive value. Conclusions In angina patients with NOCAD, CMR can objectively and noninvasively assess microvascular angina. A CMR-based combined diagnostic pathway for both epicardial and microvascular CAD deserves further clinical validation.

Development and application of endothelium-targeted microparticles for molecular magnetic resonance imaging

Molecular imaging of disease states can enhance diagnosis allowing for accurate and more effective treatment. By specifically targeting molecules differentially expressed in disease states, researchers and clinicians have a means of disease characterization at a cellular or tissue level. Targeted micron-sized particles of iron oxide (MPIO) have been used as molecule-specific contrast agents for use with magnetic resonance imaging (MRI), and early evidence suggests they may be suitable for use with other imaging modalities. Targeting of MPIO to markers of disease is commonly achieved through the covalent attachment of antibodies to the surface of the particles, providing an imaging agent that is both highly specific and which binds with high affinity. When comparing micron-sized particles with nanometre-sized particles, the former provide substantial signal dropout in MRI and confer the sensitivity to detect low levels of target. Furthermore, larger particles appear to bind to targets more potently than smaller particles. Animal models have also demonstrated favorable blood clearance characteristics of MPIO, which are important in achieving favorable signal over background and to attain clearance and disposal. Although the current generation of commercially available MPIO are not suitable for administration into humans, future work may focus on the development of biodegradable and nonimmunogenic MPIO that may allow the use of these imaging agents in a clinical setting.

Cine dyscontractility index: A novel marker of mechanical dyssynchrony that predicts response to cardiac resynchronization therapy.

To investigate whether magnetic resonance imaging (MRI) cine‐derived dyssynchrony indices provide additional information compared to conventional tagged MRI (tMRI) acquisitions in heart failure patients undergoing cardiac resynchronization therapy (CRT).