A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve.

AimsThe mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling.Materials and resultsRandomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500-1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (-3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041).ConclusionsIn this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects.Trial registrationclinicaltrials.gov Identifier: NCT01342029

Rationale and design of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary heart disease 2 trial (CE-MARC 2): a prospective, multicenter, randomized trial of diagnostic strategies in suspected coronary heart disease

Background: A number of investigative strategies exist for the diagnosis of coronary heart disease (CHD). Despite the widespread availability of noninvasive imaging, invasive angiography is commonly used early in the diagnostic pathway. Consequently, approximately 60% of angiograms reveal no evidence of obstructive coronary disease. Reducing unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. There are no large-scale comparative effectiveness trials of the different diagnostic strategies recommended in international guidelines and none that have evaluated the safety and efficacy of cardiovascular magnetic resonance.<p></p> Trial Design: CE-MARC 2 is a prospective, multicenter, 3-arm parallel group, randomized controlled trial of patients with suspected CHD (pretest likelihood 10%-90%) requiring further investigation. A total of 1,200 patients will be randomized on a 2:2:1 basis to receive 3.0-T cardiovascular magnetic resonance–guided care, single-photon emission computed tomography–guided care (according to American College of Cardiology/American Heart Association appropriate-use criteria), or National Institute for Health and Care Excellence guidelines–based management. The primary (efficacy) end point is the occurrence of unnecessary angiography as defined by a normal (>0.8) invasive fractional flow reserve. Safety of each strategy will be assessed by 3-year major adverse cardiovascular event rates. Cost-effectiveness and health-related quality-of-life measures will be performed.<p></p> Conclusions: The CE-MARC 2 trial will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intension of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, health-related quality of life, and the cost-effectiveness of CHD investigation

Magnetic resonance multitasking for motion-resolved quantitative cardiovascular imaging.

Quantitative cardiovascular magnetic resonance (CMR) imaging can be used to characterize fibrosis, oedema, ischaemia, inflammation and other disease conditions. However, the need to reduce artefacts arising from body motion through a combination of electrocardiography (ECG) control, respiration control, and contrast-weighting selection makes CMR exams lengthy. Here, we show that physiological motions and other dynamic processes can be conceptualized as multiple time dimensions that can be resolved via low-rank tensor imaging, allowing for motion-resolved quantitative imaging with up to four time dimensions. This continuous-acquisition approach, which we name cardiovascular MR multitasking, captures - rather than avoids - motion, relaxation and other dynamics to efficiently perform quantitative CMR without the use of ECG triggering or breath holds. We demonstrate that CMR multitasking allows for T1 mapping, T1-T2 mapping and time-resolved T1 mapping of myocardial perfusion without ECG information and/or in free-breathing conditions. CMR multitasking may provide a foundation for the development of setup-free CMR imaging for the quantitative evaluation of cardiovascular health

Diagnostic accuracy of 3.0-T magnetic resonance T1 and T2 mapping and T2-weighted dark-blood imaging for the infarct-related coronary artery in Non-ST-segment elevation myocardial infarction

Background: Patients with recent non–ST‐segment elevation myocardial infarction commonly have heterogeneous characteristics that may be challenging to assess clinically. Methods and Results: We prospectively studied the diagnostic accuracy of 2 novel (T1, T2 mapping) and 1 established (T2‐weighted short tau inversion recovery [T2W‐STIR]) magnetic resonance imaging methods for imaging the ischemic area at risk and myocardial salvage in 73 patients with non–ST‐segment elevation myocardial infarction (mean age 57±10 years, 78% male) at 3.0‐T magnetic resonance imaging within 6.5±3.5 days of invasive management. The infarct‐related territory was identified independently using a combination of angiographic, ECG, and clinical findings. The presence and extent of infarction was assessed with late gadolinium enhancement imaging (gadobutrol, 0.1 mmol/kg). The extent of acutely injured myocardium was independently assessed with native T1, T2, and T2W‐STIR methods. The mean infarct size was 5.9±8.0% of left ventricular mass. The infarct zone T1 and T2 times were 1323±68 and 57±5 ms, respectively. The diagnostic accuracies of T1 and T2 mapping for identification of the infarct‐related artery were similar (P=0.125), and both were superior to T2W‐STIR (P<0.001). The extent of myocardial injury (percentage of left ventricular volume) estimated with T1 (15.8±10.6%) and T2 maps (16.0±11.8%) was similar (P=0.838) and moderately well correlated (r=0.82, P<0.001). Mean extent of acute injury estimated with T2W‐STIR (7.8±11.6%) was lower than that estimated with T1 (P<0.001) or T2 maps (P<0.001). Conclusions: In patients with non–ST‐segment elevation myocardial infarction, T1 and T2 magnetic resonance imaging mapping have higher diagnostic performance than T2W‐STIR for identifying the infarct‐related artery. Compared with conventional STIR, T1 and T2 maps have superior value to inform diagnosis and revascularization planning in non–ST‐segment elevation myocardial infarction. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02073422

Cardiac magnetic resonance findings predict increased resource utilization in elective coronary artery bypass grafting

Morbidity following CABG (coronary artery bypass grafting) is difficult to predict and leads to increased healthcare costs. We hypothesized that pre-operative CMR (cardiac magnetic resonance) findings would predict resource utilization in elective CABG. Over a 12-month period, patients requiring elective CABG were invited to undergo CMR 1 day prior to CABG. Gadolinium-enhanced CMR was performed using a trueFISP inversion recovery sequence on a 1.5 tesla scanner (Sonata; Siemens). Clinical data were collected prospectively. Admission costs were quantified based on standardized actual cost/day. Admission cost greater than the median was defined as 'increased'. Of 458 elective CABG cases, 45 (10%) underwent pre-operative CMR. Pre-operative characteristics [mean (S.D.) age, 64 (9) years, mortality (1%) and median (interquartile range) admission duration, 7 (6–8) days] were similar in patients who did or did not undergo CMR. In the patients undergoing CMR, eight (18%) and 11 (24%) patients had reduced LV (left ventricular) systolic function by CMR [LVEF (LV ejection fraction) <55%] and echocardiography respectively. LE (late enhancement) with gadolinium was detected in 17 (38%) patients. The average cost/day was $2723. The median (interquartile range) admission cost was$19059 ($10891–157917). CMR LVEF {OR (odds ratio), 0.93 [95% CI (confidence interval), 0.87–0.99]; P=0.03} and SV (stroke volume) index [OR 1.07 (95% CI, 1.00–1.14); P=0.02] predicted increased admission cost. CMR LVEF (P=0.08) and EuroScore tended to predict actual admission cost (P=0.09), but SV by CMR (P=0.16) and LV function by echocardiography (P=0.95) did not. In conclusion, in this exploratory investigation, pre-operative CMR findings predicted admission duration and increased admission cost in elective CABG surgery. The cost-effectiveness of CMR in risk stratification in elective CABG surgery merits prospective assessment

Temporal dynamics and pathophysiology of the edematous response after acute myocardial infarction: a translational journey

Post-myocardial infarction tissue composition is highly dynamic and can be characterized by cardiac magnetic resonance, which has been used to assess surrogate outcomes and efficacy endpoints in many experimental and clinical studies. However, there is a paucity of studies tracking the temporal dynamics of these processes and analyzing their pathophysiology in a comprehensive manner. The experimental and clinical work contained in this dissertation shows that the degree and extent of post-myocardial infarction tissue composition changes (mainly edema; but also necrosis, hemorrhage and microvascular obstruction) as assessed by cardiac magnetic resonance are variable according to the time from infarction, duration of ischemia, cardioprotective strategies, and the interplay between them. These dynamic changes should be taken into consideration when performing image acquisition. Comparative studies should be performed at similar timings to avoid the bias of these dynamic changes. Thus, and in contrast to the accepted view, it is shown for the first time that myocardial edema in the week after ischemia/reperfusion is a bimodal phenomenon, both in pigs and humans. The initial wave of edema, appearing abruptly upon reperfusion and which is significantly attenuated at 24 hours, is due to the reperfusion process itself. The deferred wave of edema, appearing progressively days after ischemia/reperfusion and reaching a plateau between days 4 to 7, is mainly caused by the tissue healing processes. These findings highlight the need for standardizing experimental and clinical protocols for post-myocardial infarction tissue characterization aiming to quantify edema, myocardial area at risk, infarct size, myocardial salvage, intramyocardial hemorrhage and microvascular obstruction. The timeframe between day 4 and 7 post-infarction seems a good compromise solution according to translational data here presented. However, further studies and expert consensus are needed to stablish more precise recommendations