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The optimal timing of aortic valve replacement in asymptomatic patients with aortic stenosis is uncertain. Replacement fibrosis, as assessed by midwall (nonischemic) late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging, is an irreversible marker of left ventricular decompensation in aortic stenosis. Once established, it progresses rapidly and is associated with poor long-term prognosis in a dose-dependent manner. The objective of this multicenter prospective randomized controlled trial is to determine whether early aortic valve replacement in asymptomatic patients with severe aortic stenosis can improve the adverse prognosis associated with midwall LGE. Patients will be screened for likelihood of having LGE with electrocardiography or high-sensitivity troponin I. Those at high risk will proceed to CMR imaging. Approximately 400 patients with midwall LGE will be randomized 1:1 to early valve replacement or routine care. Those who do not exhibit midwall LGE will continue with routine care and be randomized to a study registry or no further follow-up. Follow-up will be annual for approximately 3 years until the number of required outcome events is achieved. The primary endpoint is a composite of all-cause mortality and unplanned aortic stenosis–related hospitalization. The expected event rate is 25.0% in the routine care arm and 13.4% in the early intervention arm over the first 2 years; 88 observed primary outcome events will give 90% power at 5% significance level. Key secondary endpoints include all-cause mortality, sudden cardiac death, stroke, and symptomatic status. The EVOLVED trial is the first multicenter randomized controlled trial to compare early aortic valve replacement to routine care in asymptomatic patients with severe aortic stenosis and midwall LGE.

Cardiovascular cine magnetic resonance (CMR) accelerated by compressed sensing (CS) is used to assess left ventricular (LV) function. However, it is difficult for prospective CS cine CMR to capture the complete end-diastolic phase, which can lead to underestimation of the end-diastolic volume (EDV), stroke volume (SV), and ejection fraction (EF), compared to retrospective standard cine CMR. This prospective study aimed to evaluate the diagnostic quality and accuracy of single-breath-hold full cardiac cycle CS cine CMR, acquired over two heart beats, to quantify LV volume in comparison to multi-breath-hold standard cine CMR. Eighty-one participants underwent standard segmented breath-hold cine and CS real-time cine CMR examinations to obtain a stack of eight contiguous short-axis images with same high spatial (1.7 × 1.7 mm2) and temporal resolution (41 ms). Two radiologists independently performed qualitative analysis of image quality (score, 1 [i.e., “nondiagnostic”] to 5 [i.e., “excellent”]) and quantitative analysis of the LV volume measurements. The total examination time was 113 ± 7 s for standard cine CMR and 24 ± 4 s for CS cine CMR (p < 0.0001). The CS cine image quality was slightly lower than standard cine (4.8 ± 0.5 for standard vs. 4.4 ± 0.5 for CS; p < 0.0001). However, all image quality scores for CS cine were above 4 (i.e., good). No significant differences existed between standard and CS cine MR for all quantitative LV measurements. The mean differences with 95 % confidence interval (CI), based on Bland–Altman analysis, were 1.3 mL (95 % CI, −14.6 – 17.2) for LV end-diastolic volume, 0.2 mL (95 % CI, −9.8 to10.3) for LV end-systolic volume, 1.1 mL (95 % CI, −10.5 to 12.7) for LV stroke volume, 1.0 g (95 % CI, −11.2 to 13.3) for LV mass, and 0.4 % (95 % CI, −4.8 – 5.6) for LV ejection fraction. The interobserver and intraobserver variability for CS cine MR ranged from −4.8 – 1.6 % and from −7.3 – 9.3 %, respectively, with slopes of the regressions ranging 0.88–1.0 and 0.86–1.03, respectively. Single-breath-hold full cardiac cycle CS real-time cine CMR could evaluate LV volume with excellent accuracy. It may replace multi-breath-hold standard cine CMR.

Melatonin, an endogenously produced hormone, might potentially limit the ischemia reperfusion injury and improve the efficacy of mechanical reperfusion with primary percutaneous coronary intervention (pPCI) in ST-segment elevation myocardial infarction (STEMI). This study was aimed to evaluate whether the treatment effect of melatonin therapy in patients with STEMI is influenced by the time to administration. We performed a post hoc analysis of the Melatonin Adjunct in the Acute Myocardial Infarction Treated With Angioplasty trial (NCT00640094), which randomized STEMI patients to melatonin (intravenous and intracoronary bolus) or placebo during pPCI. Randomized patients were divided into tertiles according to symptoms onset to balloon time: first tertile (136 ± 23 minutes), second tertile (196 ± 19 minutes), and third tertile (249 ± 41 minutes). Magnetic resonance imaging was performed within 1 week after pPCI. A total of 146 patients presenting with STEMI within 360 minutes of chest pain onset were randomly allocated to intravenous and intracoronary melatonin or placebo during pPCI. In the first tertile, the infarct size was significantly smaller in the melatonin-treated subjects compared with placebo (14.6 ± 14.2 vs 24.9 ± 9.0%; p = 0.003). Contrariwise, treatment with melatonin was associated with a larger infarct size in the group of patients included in the third tertile (20.5 ± 8.7% vs 11.2 ± 5.2%; p = 0.001), resulting in a significant interaction (p = 0.001). In conclusion, the administration of melatonin in patients with STEMI who presented early after symptom onset was associated with a significant reduction in the infarct size after pPCI.

We aimed to determine whether the myocardial extracellular volume (ECV), measured using T1 measurements obtained during cardiac magnetic resonance imaging were increased in patients treated with anthracyclines. We performed cardiac magnetic resonance imaging and echocardiography and measured the ECV in 42 patients treated with anthracyclines. The data from the cardiac magnetic resonance study were compared to those from healthy volunteers. The anthracycline-treated cohort consisted of 21 men and 21 women with a mean age of 55 ± 17 years, who presented a median of 84 months after chemotherapy with a cumulative anthracycline exposure of 282 ± 65 mg/m2 and a mean left ventricular ejection fraction of 52 ± 12%. The ECV was elevated in the anthracycline-treated patients compared to the age- and gender-matched controls (0.36 ± 0.03 vs 0.28 ± 0.02, p <0.001). A positive association was found between the ECV and left atrial volume (ECV vs indexed left atrial volume, r = 0.65, p <0.001), and negative association was found between the ECV and diastolic function (E′ lateral, r = −0.64, p <0.001). In conclusion, the myocardial ECV is elevated in patients with previous anthracycline treatment and is associated with the diastolic function and increased atrial volumes.

BackgroundDuring primary percutaneous coronary intervention (PCI), a concurrent chronic total occlusion (CTO) is found in 10% of patients with ST-elevation myocardial infarction (STEMI). Long-term benefits of CTO-PCI have been suggested; however, randomised data are lacking. Our aim was to determine mid-term and long-term clinical outcome of CTO-PCI versus CTO-No PCI in patients with STEMI with a concurrent CTO.MethodsThe Evaluating Xience and left ventricular function in PCI on occlusiOns afteR STEMI (EXPLORE) was a multicentre randomised trial that included 302 patients with STEMI after successful primary PCI with a concurrent CTO. Patients were randomised to either CTO-PCI or CTO-No PCI. The primary end point of the current study was occurrence of major adverse cardiac events (MACE): cardiac death, coronary artery bypass grafting and MI. Other end points were 1-year left ventricular function (LVF); LV-ejection fraction and LV end-diastolic volume and angina status.ResultsThe median long-term follow-up was 3.9 (2.1–5.0) years. MACE was not significantly different between both arms (13.5% vs 12.3%, HR 1.03, 95% CI 0.54 to 1.98; P=0.93). Cardiac death was more frequent in the CTO-PCI arm (6.0% vs 1.0%, P=0.02) with no difference in all-cause mortality (12.9% vs 6.2%, HR 2.07, 95% CI 0.84 to 5.14; P=0.11). One-year LVF did not differ between both arms. However, there were more patients with freedom of angina in the CTO-PCI arm at 1 year (94% vs 87%, P=0.03).ConclusionsIn this randomised trial involving patients with STEMI with a concurrent CTO, CTO-PCI was not associated with a reduction in long-term MACE compared to CTO-No PCI. One-year LVF was comparable between both treatment arms. The finding that there were more patients with freedom of angina after CTO-PCI at 1-year follow-up needs further investigation.Clinical trial registrationEXPLORE trial number NTR1108 www.trialregister.nl.

ObjectiveTo evaluate the effect of prereperfusion hypothermia initiated in the out-of-hospital setting in awake patients with ST-segment elevation myocardial infarction (STEMI) on myocardial salvage measured by cardiac MRI (CMR).MethodsHypothermia was initiated within 6 hours of symptom onset by the emergency medical service with surface cooling pads and cold saline, and continued in the cath lab with endovascular cooling (target temperature: ≤35°C at time of reperfusion). Myocardial salvage index (using CMR) was compared in a randomised, controlled, open-label, endpoint blinded trial to a not-cooled group of patients at day 4±2 after the event.ResultsAfter postrandomisation exclusion of 19 patients a total of 101 patients were included in the intention-to-treat analysis (control group: n=54; hypothermia group: n=47). Target temperature was reached in 38/47 patients (81%) in the intervention group. Study-related interventions resulted in a delay in time from first medical contact to reperfusion of 14 min (control group 89±24 min; hypothermia group 103±21 min; p<0.01). Myocardial salvage index was 0.37 (±0.26) in the control group and 0.43 (±0.27) in the hypothermia group (p=0.27). No differences in cardiac biomarkers or clinical outcomes were found. In a CMR follow-up 6 months after the initial event no significant differences were detected.ConclusionOut-of-hospital induced therapeutic hypothermia as an adjunct to primary percutaneous coronary intervention did not improve myocardial salvage in patients with STEMI.Trial registration number NCT01777750

Coronary computed tomography angiography (CTA) is the preferred primary diagnostic modality when examining patients with low to intermediate pre-test probability of coronary artery disease (CAD). Only 20-30% of these have potentially obstructive CAD. Because of the relatively poor positive predictive value of coronary CTA, unnecessary invasive coronary angiographies (ICAs) are conducted with the costs and risks associated with the procedure. Hence, an optimized diagnostic CAD algorithm may reduce the numbers of ICAs not followed by revascularization. The Dan-NICAD 2 study has 3 equivalent main aims: (1) To examine the diagnostic precision of a sound-based diagnostic algorithm, The CADScor®System (Acarix A/S, Denmark), in patients with a low to intermediate pre-test risk of CAD referred to a primary examination by coronary CTA. We hypothesize that the CADScor®System provides better stratification prior to coronary CTA than clinical risk stratification scores alone. (2) To compare the diagnostic accuracy of 3T cardiac magnetic resonance imaging (3T CMRI), 82rubidium positron emission tomography (82Rb-PET), and CT-derived fractional flow reserve (FFRCT) in patients where obstructive CAD cannot be ruled out by coronary CTA using ICA fractional flow reserve (FFR) as reference standard. (3) To compare the diagnostic performance of quantitative flow ratio (QFR) and ICA-FFR in patients with low to intermediate pre-test probability of CAD using 82Rb-PET as reference standard. Dan-NICAD 2 is a prospective, multicenter, cross-sectional study including approximately 2,000 patients with low to intermediate pre-test probability of CAD and without previous history of CAD. Patients are referred to coronary CTA because of symptoms suggestive of CAD, as evaluated by a cardiologist. Patient interviews, sound recordings, and blood samples are obtained in connection with the coronary CTA. If coronary CTA does not rule out obstructive CAD, patients will be examined by 3T CMRI 82Rb-PET, FFRCT, ICA, and FFR. Reference standard is ICA-FFR. Obstructive CAD is defined as an FFR ≤0.80 or as high-grade stenosis (>90% diameter stenosis) by visual assessment. Diagnostic performance will be evaluated as sensitivity, specificity, predictive values, likelihood ratios, calibration, and discrimination. Enrolment started January 2018 and is expected to be completed by June 2020. Patients are followed for 10 years after inclusion. The results of the Dan-NICAD 2 study are expected to contribute to the improvement of diagnostic strategies for patients suspected of CAD in 3 different steps: risk stratification prior to coronary CTA, diagnostic strategy after coronary CTA, and invasive wireless QFR analysis as an alternative to ICA-FFR.

Perfusion-cardiovascular magnetic resonance (CMR) is generally accepted as an alternative to SPECT to assess myocardial ischemia non-invasively. However its performance vs gated-SPECT and in sub-populations is not fully established. The goal was to compare in a multicenter setting the diagnostic performance of perfusion-CMR and gated-SPECT for the detection of CAD in various populations using conventional x-ray coronary angiography (CXA) as the standard of reference. In 33 centers (in US and Europe) 533 patients, eligible for CXA or SPECT, were enrolled in this multivendor trial. SPECT and CXA were performed within 4 weeks before or after CMR in all patients. Prevalence of CAD in the sample was 49% and 515 patients received MR contrast medium. Drop-out rates for CMR and SPECT were 5.6% and 3.7%, respectively (ns). The study was powered for the primary endpoint of non-inferiority of CMR vs SPECT for both, sensitivity and specificity for the detection of CAD (using a single-threshold reading), the results for the primary endpoint were reported elsewhere. In this article secondary endpoints are presented, i.e. the diagnostic performance of CMR versus SPECT in subpopulations such as multi-vessel disease (MVD), in men, in women, and in patients without prior myocardial infarction (MI). For diagnostic performance assessment the area under the receiver-operator-characteristics-curve (AUC) was calculated. Readers were blinded versus clinical data, CXA, and imaging results. The diagnostic performance (= area under ROC = AUC) of CMR was superior to SPECT (p = 0.0004, n = 425) and to gated-SPECT (p = 0.018, n = 253). CMR performed better than SPECT in MVD (p = 0.003 vs all SPECT, p = 0.04 vs gated-SPECT), in men (p = 0.004, n = 313) and in women (p = 0.03, n = 112) as well as in the non-infarct patients (p = 0.005, n = 186 in 1–3 vessel disease and p = 0.015, n = 140 in MVD). In this large multicenter, multivendor study the diagnostic performance of perfusion-CMR to detect CAD was superior to perfusion SPECT in the entire population and in sub-groups. Perfusion-CMR can be recommended as an alternative for SPECT imaging. ClinicalTrials.gov, Identifier: NCT00977093

IntroductionThere is conflicting evidence regarding the benefits of percutaneous coronary intervention (PCI) in patients with grey zone fractional flow reserve (GZFFR artery) values (0.75–0.80). The prevalence of ischaemia is unknown. We wished to define the prevalence of ischaemia in GZFFR artery and assess whether PCI is superior to optimal medical therapy (OMT) for angina control.MethodsWe enrolled 104 patients with angina with 1:1 randomisation to PCI or OMT. The artery was interrogated with a Doppler flow/pressure wire. Patients underwent Magnetic Resonance Imaging (MRI) with follow-up at 3 and 12 months. The primary outcome was angina status at 3 months using the Seattle Angina Questionnaire (SAQ).Results104 patients (age 60±9 years), 79 (76%) males and 79 (76%) Left Anterior Descending (LAD) stenoses were randomised. Coronary physiology and SAQ were similar. Of 98 patients with stress perfusion MRI data, 17 (17%) had abnormal perfusion (≥2 segments with ≥25% ischaemia or ≥1 segment with ≥50% ischaemia) in the target GZFFR artery. Of 89 patients with invasive physiology data, 26 (28%) had coronary flow velocity reserve <2.0 in the target GZFFR artery. After 3 months of follow-up, compared with patients treated with OMT only, patients treated by PCI and OMT had greater improvements in SAQ angina frequency (21 (28) vs 10 (23); p=0.026) and quality of life (24 (26) vs 11 (24); p=0.008) though these differences were no longer significant at 12 months.ConclusionsNon-invasive evidence of major ischaemia is uncommon in patients with GZFFR artery. Compared with OMT alone, patients randomised to undergo PCI reported improved symptoms after 3 months but these differences were no longer significant after 12 months.Trial registration number NCT02425969.

ObjectivesReperfusion immediately after reopening of the infarct-related artery in ST-segment elevation myocardial infarction (STEMI) may cause myocardial damage in addition to the ischaemic insult (reperfusion injury). The gap junction modulating peptide danegaptide has in animal models reduced this injury. We evaluated the effect of danegaptide on myocardial salvage in patients with STEMI.MethodsIn addition to primary percutaneous coronary intervention in STEMI patients with thrombolysis in myocardial infarction flow 0–1, single vessel disease and ischaemia time less than 6 hours, we tested, in a clinical proof-of-concept study, the therapeutic potential of danegaptide at two-dose levels. Primary outcome was myocardial salvage evaluated by cardiac MRI after 3 months.ResultsFrom November 2013 to August 2015, a total of 585 patients were randomly enrolled in the trial. Imaging criteria were fulfilled for 79 (high dose), 80 (low dose) and 84 (placebo) patients eligible for the per-protocol analysis. Danegaptide did not affect the myocardial salvage index (danegaptide high (63.9±14.9), danegaptide low (65.6±15.6) and control (66.7±11.7), P=0.40), final infarct size (danegaptide high (19.6±11.4 g), danegaptide low (18.6±9.6 g) and control (21.4±15.0 g), P=0.88) or left ventricular ejection fraction (danegaptide high (53.9%±9.5%), danegaptide low (52.7%±10.3%) and control (52.1%±10.9%), P=0.64). There was no difference between groups with regard to clinical outcome.ConclusionsAdministration of danegaptide to patients with STEMI did not improve myocardial salvage.Trial registration number NCT01977755; Pre-results.