Extracorporeal Life Support in Infarct-Related Cardiogenic Shock.

BACKGROUND: Extracorporeal life support (ECLS) is increasingly used in the treatment of infarct-related cardiogenic shock despite a lack of evidence regarding its effect on mortality. METHODS: In this multicenter trial, patients with acute myocardial infarction complicated by cardiogenic shock for whom early revascularization was planned were randomly assigned to receive early ECLS plus usual medical treatment (ECLS group) or usual medical treatment alone (control group). The primary outcome was death from any cause at 30 days. Safety outcomes included bleeding, stroke, and peripheral vascular complications warranting interventional or surgical therapy. RESULTS: A total of 420 patients underwent randomization, and 417 patients were included in final analyses. At 30 days, death from any cause had occurred in 100 of 209 patients (47.8%) in the ECLS group and in 102 of 208 patients (49.0%) in the control group (relative risk, 0.98; 95% confidence interval [CI], 0.80 to 1.19; P = 0.81). The median duration of mechanical ventilation was 7 days (interquartile range, 4 to 12) in the ECLS group and 5 days (interquartile range, 3 to 9) in the control group (median difference, 1 day; 95% CI, 0 to 2). The safety outcome consisting of moderate or severe bleeding occurred in 23.4% of the patients in the ECLS group and in 9.6% of those in the control group (relative risk, 2.44; 95% CI, 1.50 to 3.95); peripheral vascular complications warranting intervention occurred in 11.0% and 3.8%, respectively (relative risk, 2.86; 95% CI, 1.31 to 6.25). CONCLUSIONS: In patients with acute myocardial infarction complicated by cardiogenic shock with planned early revascularization, the risk of death from any cause at the 30-day follow-up was not lower among the patients who received ECLS therapy than among those who received medical therapy alone. (Funded by the Else Kröner Fresenius Foundation and others; ECLS-SHOCK ClinicalTrials.gov number, NCT03637205.).

Rest and exercise-stress estimated pulmonary capillary wedge pressure using real-time free-breathing cardiovascular magnetic resonance imaging.

BACKGROUND: Identification of increased pulmonary capillary wedge pressure (PCWP) by right heart catheterization (RHC) is the reference standard for the diagnosis of heart failure with preserved ejection fraction (HFpEF). Recently, cardiovascular magnetic resonance (CMR) imaging estimation of PCWP at rest was introduced as a non-invasive alternative. Since many patients are only identified during physiological exercise-stress, we hypothesized that novel exercise-stress CMR-derived PCWP emerges superior compared to its assessment at rest. METHODS: The HFpEF-Stress Trial prospectively recruited 75 patients with exertional dyspnea and diastolic dysfunction who then underwent rest and exercise-stress RHC and CMR. HFpEF was defined according to PCWP (overt HFpEF ≥15 mmHg at rest, masked HFpEF ≥25 mmHg during exercise-stress). CMR-derived PCWP was calculated based on previously published formula using left ventricular mass and either biplane left atrial volume (LAV) or monoplane left atrial area (LAA). RESULTS: LAV (rest/stress: r = 0.50/r = 0.55, p < 0.001) and LAA PCWP (rest/stress: r = 0.50/r = 0.48, p < 0.001) correlated significantly with RHC-derived PCWP while numerically overestimating PCWP at rest and underestimating PCWP during exercise-stress. LAV and LAA PCWP showed good diagnostic accuracy to detect HFpEF (area under the receiver operating characteristic curve (AUC) LAV rest 0.73, stress 0.81; LAA rest 0.72, stress 0.77) with incremental diagnostic value for the detection of masked HFpEF using exercise-stress (AUC LAV rest 0.54 vs stress 0.67, p = 0.019, LAA rest 0.52 vs stress 0.66, p = 0.012). LAV but not LAA PCWP during exercise-stress was a predictor for 24 months hospitalization independent of a medical history for atrial fibrillation (hazard ratio (HR) 1.26, 95% confidence interval 1.02-1.55, p = 0.032). CONCLUSION: Non-invasive PCWP correlates well with the invasive reference at rest and during exercise stress. There is overall good diagnostic accuracy for HFpEF assessment using CMR-derived estimated PCWP despite deviations in absolute agreement. Non-invasive exercise derived PCWP may particularly facilitate detection of masked HFpEF in the future.

Cardiovascular magnetic resonance rest and exercise-stress left atrioventricular coupling index to detect diastolic dysfunction.

Left atrial and ventricular (LA/LV) dysfunction are interlinked in heart failure with preserved ejection fraction (HFpEF); however, little is known about their interplay and relation to cardiac decompensation. We hypothesized that cardiovascular magnetic resonance (CMR) left atrioventricular coupling index (LACI) would identify pathophysiological alterations in HFpEF and be amenable to rest and ergometer-stress CMR. Patients with exertional dyspnoea, signs of diastolic dysfunction (E/e' ≥ 8), and preserved ejection fraction (EF; ≥50%) on echocardiography were prospectively recruited and classified as HFpEF (n = 34) or noncardiac dyspnoea (NCD, n = 34) according to pulmonary capillary wedge pressure (PCWP) on right-heart catheterization (rest/stress ≥ 15/25 mmHg). LA and LV volumes were assessed on short-axis real-time cine sequences at rest and during exercise stress. LACI was defined as the ratio of the LA-to-LV end-diastolic volume. Cardiovascular hospitalization (CVH) was assessed after 24 mo. Volume-derived LA (P ≥ 0.008) but not LV (P ≥ 0.347) morphology and function at rest and during exercise stress detected significant differences comparing HFpEF and NCD. There was impaired atrioventricular coupling in HFpEF at rest (LACI, 45.7% vs. 31.6%, P < 0.001) and during exercise stress (45.7% vs. 27.9%, P < 0.001). LACI correlated with PCWP at rest (r = 0.48, P < 0.001) and during exercise stress (r = 0.55, P < 0.001). At rest, LACI was the only volumetry-derived parameter to differentiate patients with NCD from patients with HFpEF, which were identified using exercise-stress thresholds (P = 0.001). Resting and exercise-stress LACI dichotomized at their medians were associated with CVH (P ≤ 0.005). Assessment of LACI is a simple approach for LA/LV coupling quantification and allows easy and fast identification of heart failure with preserved ejection fraction (HFpEF).NEW & NOTEWORTHY Evaluation of the left atrioventricular coupling index (LACI) in a rest and exercise-stress cardiovascular magnetic resonance imaging protocol allows identification of patients with heart failure and preserved ejection fraction with high diagnostic accuracy. LACI holds similar diagnostic accuracy at rest compared with left atrial ejection fraction during exercise stress. This highlights the value of LACI as a widely available and cost-effective test for diastolic dysfunction, which may help to guide patient selection for referral to specialized testing/treatment.

Cardiovascular magnetic resonance-derived left atrioventricular coupling index and major adverse cardiac events in patients following acute myocardial infarction.

BACKGROUND: Recently, a novel left atrioventricular coupling index (LACI) has been introduced providing prognostic value to predict cardiovascular events beyond common risk factors in patients without cardiovascular disease. Since data on cardiovascular magnetic resonance (CMR)-derived LACI in patients following acute myocardial infarction (AMI) are scarce, we aimed to assess the diagnostic and prognostic implications of LACI in a large AMI patient cohort. METHODS: In total, 1046 patients following AMI were included. After primary percutaneous coronary intervention CMR imaging and subsequent functional analyses were performed. LACI was defined by the ratio of the left atrial end-diastolic volume divided by the left ventricular (LV) end-diastolic volume. Major adverse cardiac events (MACE) including death, reinfarction or heart failure within 12 months after the index event were defined as primary clinical endpoint. RESULTS: LACI was significantly higher in patients with MACE compared to those without MACE (p < 0.001). Youden Index identified an optimal LACI cut-off at 34.7% to classify patients at high-risk (p < 0.001 on log-rank testing). Greater LACI was associated with MACE on univariate regression modeling (HR 8.1, 95% CI 3.4-14.9, p < 0.001) and after adjusting for baseline confounders and LV ejection fraction (LVEF) on multivariate regression analyses (HR 3.1 95% CI 1.0-9, p = 0.049). Furthermore, LACI assessment enabled further risk stratification in high-risk patients with impaired LV systolic function (LVEF ≤ 35%; p < 0.001 on log-rank testing). CONCLUSION: Atrial-ventricular interaction using CMR-derived LACI is a superior measure of outcome beyond LVEF especially in high-risk patients following AMI. Trial registration ClinicalTrials.gov, NCT00712101 and NCT01612312.

Exercise Stress Real-Time Cardiac Magnetic Resonance Imaging for Noninvasive Characterization of Heart Failure With Preserved Ejection Fraction: The HFpEF-Stress Trial.

BACKGROUND: Right heart catheterization using exercise stress is the reference standard for the diagnosis of heart failure with preserved ejection fraction (HFpEF) but carries the risk of the invasive procedure. We hypothesized that real-time cardiac magnetic resonance (RT-CMR) exercise imaging with pathophysiologic data at excellent temporal and spatial resolution may represent a contemporary noninvasive alternative for diagnosing HFpEF. METHODS: The HFpEF-Stress trial (CMR Exercise Stress Testing in HFpEF; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621. URL: https://dzhk.de/; Unique identifier: DZHK-17) prospectively recruited 75 patients with echocardiographic signs of diastolic dysfunction and dyspnea on exertion (E/e'>8, New York Heart Association class ≥II) to undergo echocardiography, right heart catheterization, and RT-CMR at rest and during exercise stress. HFpEF was defined according to pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during exercise stress). RT-CMR functional assessments included time-volume curves for total and early (1/3) diastolic left ventricular filling, left atrial (LA) emptying, and left ventricular/LA long axis strain. RESULTS: Patients with HFpEF (n=34; median pulmonary capillary wedge pressure at rest, 13 mm Hg; at stress, 27 mm Hg) had higher E/e' (12.5 versus 9.15), NT-proBNP (N-terminal pro-B-type natriuretic peptide; 255 versus 75 ng/L), and LA volume index (43.8 versus 36.2 mL/m2) compared with patients with noncardiac dyspnea (n=34; rest, 8 mm Hg; stress, 18 mm Hg; P≤0.001 for all). Seven patients were excluded because of the presence of non-HFpEF cardiac disease causing dyspnea on imaging. There were no differences in RT-CMR left ventricular total and early diastolic filling at rest and during exercise stress (P≥0.164) between patients with HFpEF and noncardiac dyspnea. RT-CMR revealed significantly impaired LA total and early (P<0.001) diastolic emptying in patients with HFpEF during exercise stress. RT-CMR exercise stress LA long axis strain was independently associated with HFpEF (adjusted odds ratio, 0.657 [95% CI, 0.516-0.838]; P=0.001) after adjustment for clinical and imaging measures and emerged as the best predictor for HFpEF (area under the curve at rest 0.82 versus exercise stress 0.93; P=0.029). CONCLUSIONS: RT-CMR allows highly accurate identification of HFpEF during physiologic exercise and qualifies as a suitable noninvasive diagnostic alternative. These results will need to be confirmed in multicenter prospective research studies to establish widespread routine clinical use. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621. URL: https://dzhk.de/; Unique identifier: DZHK-17.

Artificial Intelligence Enabled Fully Automated CMR Function Quantification for Optimized Risk Stratification in Patients Undergoing Transcatheter Aortic Valve Replacement.

Background: Cardiovascular magnetic resonance imaging is considered the reference standard for assessing cardiac morphology and function and has demonstrated prognostic utility in patients undergoing transcatheter aortic valve replacement (TAVR). Novel fully automated analyses may facilitate data analyses but have not yet been compared against conventional manual data acquisition in patients with severe aortic stenosis (AS). Methods: Fully automated and manual biventricular assessments were performed in 139 AS patients scheduled for TAVR using commercially available software (suiteHEART®, Neosoft; QMass®, Medis Medical Imaging Systems). Volumetric assessment included left ventricular (LV) mass, LV/right ventricular (RV) end-diastolic/end-systolic volume, LV/RV stroke volume, and LV/RV ejection fraction (EF). Results of fully automated and manual analyses were compared. Regression analyses and receiver operator characteristics including area under the curve (AUC) calculation for prediction of the primary study endpoint cardiovascular (CV) death were performed. Results: Fully automated and manual assessment of LVEF revealed similar prediction of CV mortality in univariable (manual: hazard ratio (HR) 0.970 (95% CI 0.943-0.997) p=0.032; automated: HR 0.967 (95% CI 0.939-0.995) p=0.022) and multivariable analyses (model 1: (including significant univariable parameters) manual: HR 0.968 (95% CI 0.938-0.999) p=0.043; automated: HR 0.963 [95% CI 0.933-0.995] p=0.024; model 2: (including CV risk factors) manual: HR 0.962 (95% CI 0.920-0.996) p=0.027; automated: HR 0.954 (95% CI 0.920-0.989) p=0.011). There were no differences in AUC (LVEF fully automated: 0.686; manual: 0.661; p=0.21). Absolute values of LV volumes differed significantly between automated and manual approaches (p < 0.001 for all). Fully automated quantification resulted in a time saving of 10 minutes per patient. Conclusion: Fully automated biventricular volumetric assessments enable efficient and equal risk prediction compared to conventional manual approaches. In addition to significant time saving, this may provide the tools for optimized clinical management and stratification of patients with severe AS undergoing TAVR.

Functional and structural reverse myocardial remodeling following transcatheter aortic valve replacement: a prospective cardiovascular magnetic resonance study.

BACKGROUND: Since cardiovascular magnetic resonance (CMR) imaging allows comprehensive quantification of both myocardial function and structure we aimed to assess myocardial remodeling processes in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). METHODS: CMR imaging was performed in 40 patients with severe AS before and 1 year after TAVR. Image analyses comprised assessments of myocardial volumes, CMR-feature-tracking based atrial and ventricular strain, myocardial T1 mapping, extracellular volume fraction-based calculation of left ventricular (LV) cellular and matrix volumes, as well as ischemic and non-ischemic late gadolinium enhancement analyses. Moreover, biomarkers including NT-proBNP as well as functional and clinical status were documented. RESULTS: Myocardial function improved 1 year after TAVR: LV ejection fraction (57.9 ± 16.9% to 65.4 ± 14.5%, p = 0.002); LV global longitudinal (- 21.4 ± 8.0% to -25.0 ± 6.4%, p < 0.001) and circumferential strain (- 36.9 ± 14.3% to - 42.6 ± 11.8%, p = 0.001); left atrial reservoir (13.3 ± 6.3% to 17.8 ± 6.7%, p = 0.001), conduit (5.5 ± 3.2% to 8.4 ± 4.6%, p = 0.001) and boosterpump strain (8.2 ± 4.6% to 9.9 ± 4.2%, p = 0.027). This was paralleled by regression of total myocardial volume (90.3 ± 21.0 ml/m2 to 73.5 ± 17.0 ml/m2, p < 0.001) including cellular (55.2 ± 13.2 ml/m2 to 45.3 ± 11.1 ml/m2, p < 0.001) and matrix volumes (20.7 ± 6.1 ml/m2 to 18.8 ± 5.3 ml/m2, p = 0.036). These changes were paralleled by recovery from heart failure (decrease of NYHA class: p < 0.001; declining NT-proBNP levels: 2456 ± 3002 ng/L to 988 ± 1222 ng/L, p = 0.001). CONCLUSION: CMR imaging enables comprehensive detection of myocardial remodeling in patients undergoing TAVR. Regression of LV matrix volume as a surrogate for reversible diffuse myocardial fibrosis is accompanied by increase of myocardial function and recovery from heart failure. Further data are required to define the value of these parameters as therapeutic targets for optimized management of TAVR patients. Trial registration DRKS, DRKS00024479. Registered 10 December 2021-Retrospectively registered, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024479.

Head-to-head comparison of cardiovascular MR feature tracking cine versus acquisition-based deformation strain imaging using myocardial tagging and strain encoding.

PURPOSE: Myocardial feature-tracking (FT) deformation imaging is superior for risk stratification compared with volumetric approaches. Because there is no clear recommendation regarding FT postprocessing, we compared different FT-strain analyses with reference standard techniques, including tagging and strain-encoded (SENC) MRI. METHODS: Feature-tracking software from four different vendors (TomTec, Medis, Circle [CVI], and Neosoft), tagging (Segment), and fastSENC (MyoStrain) were used to determine left ventricular global circumferential strains (GCS) and longitudinal strains (GLS) in 12 healthy volunteers and 12 patients with heart failure. Variability and agreements were assessed using intraclass correlation coefficients for absolute agreement (ICCa) and consistency (ICCc) as well as Pearson correlation coefficients. RESULTS: For FT-GCS, consistency was excellent comparing different FT vendors (ICCc = 0.84-0.97, r = 0.86-0.95) and in comparison to fast SENC (ICCc = 0.78-0.89, r = 0.73-0.81). FT-GCS consistency was excellent compared with tagging (ICCc = 0.79-0.85, r = 0.74-0.77) except for TomTec (ICCc = 0.68, r = 0.72). Absolute FT-GCS agreements among FT vendors were highest for CVI and Medis (ICCa = 0.96) and lowest for TomTec and Neosoft (ICCa = 0.32). Similarly, absolute FT-GCS agreements were excellent for CVI and Medis compared with both tagging and fast SENC (ICCa = 0.84-0.88), good to excellent for Neosoft (ICCa = 0.77 and 0.64), and lowest for TomTec (ICCa = 0.41 and 0.47). For FT-GLS, consistency was excellent (ICCc ≥ 0.86, r ≥ 0.76). Absolute agreements among FT vendors were excellent (ICCa = 0.91-0.93) or good to excellent for TomTec (ICCa = 0.69-0.85). Absolute agreements (ICCa) were good (CVI 0.70, Medis 0.60) and fair (TomTec 0.41, Neosoft 0.59) compared with tagging, but excellent compared with fast SENC (ICCa = 0.77-0.90). CONCLUSION: Although absolute agreements differ depending on deformation assessment approaches, consistency and correlation are consistently high regardless of the method chosen, thus indicating reliable strain assessment. Further standardisation and introduction of uniform references is warranted for routine clinical implementation.

Myocardial mechanics in dilated cardiomyopathy: prognostic value of left ventricular torsion and strain.

BACKGROUND: Data on the prognostic value of left ventricular (LV) morphological and functional parameters including LV rotation in patients with dilated cardiomyopathy (DCM) using cardiovascular magnetic resonance (CMR) are currently scarce. In this study, we assessed the prognostic value of global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS) and LV torsion using CMR feature tracking (FT). METHODS: CMR was performed in 350 DCM patients and 70 healthy subjects across 5 different European CMR Centers. Myocardial strain parameters were retrospectively assessed from conventional balanced steady-state free precession cine images applying FT. A combined primary endpoint (cardiac death, heart transplantation, aborted sudden cardiac death) was defined for the assessment of clinical outcome. RESULTS: GLS, GCS, GRS and LV torsion were significantly lower in DCM patients than in healthy subjects (all p < 0.001). The primary endpoint occurred in 59 (18.7%) patients [median follow-up 4.2 (2.0-5.6) years]. In the univariate analyses all strain parameters showed a significant prognostic value (p < 0.05). In the multivariate model, LV strain parameters, particularly GLS provided an incremental prognostic value compared to established CMR parameters like LV ejection fraction and late gadolinium enhancement. A scoring model including six categorical variables of standard CMR and strain parameters differentiated further risk subgroups. CONCLUSION: LV strain assessed with CMR FT has a high prognostic value in patients with DCM, surpassing routine and dedicated functional parameters. Thus, CMR strain imaging may contribute to the improvement of risk stratification in DCM.

Defining the optimal temporal and spatial resolution for cardiovascular magnetic resonance imaging feature tracking.

BACKGROUND: Myocardial deformation analyses using cardiovascular magnetic resonance (CMR) feature tracking (CMR-FT) have incremental value in the assessment of cardiac function beyond volumetric analyses. Since guidelines do not recommend specific imaging parameters, we aimed to define optimal spatial and temporal resolutions for CMR cine images to enable reliable post-processing. METHODS: Intra- and inter-observer reproducibility was assessed in 12 healthy subjects and 9 heart failure (HF) patients. Cine images were acquired with different temporal (20, 30, 40 and 50 frames/cardiac cycle) and spatial resolutions (high in-plane 1.5 × 1.5 mm through-plane 5 mm, standard 1.8 × 1.8 x 8mm and low 3.0 × 3.0 x 10mm). CMR-FT comprised left ventricular (LV) global and segmental longitudinal/circumferential strain (GLS/GCS) and associated systolic strain rates (SR), and right ventricular (RV) GLS. RESULTS: Temporal but not spatial resolution did impact absolute strain and SR. Maximum absolute changes between lowest and highest temporal resolution were as follows: 1.8% and 0.3%/s for LV GLS and SR, 2.5% and 0.6%/s for GCS and SR as well as 1.4% for RV GLS. Changes of strain values occurred comparing 20 and 30 frames/cardiac cycle including LV and RV GLS and GCS (p < 0.001-0.046). In contrast, SR values (LV GLS/GCS SR) changed significantly comparing all successive temporal resolutions (p < 0.001-0.013). LV strain and SR reproducibility was not affected by either temporal or spatial resolution, whilst RV strain variability decreased with augmentation of temporal resolution. CONCLUSION: Temporal but not spatial resolution significantly affects strain and SR in CMR-FT deformation analyses. Strain analyses require lower temporal resolution and 30 frames/cardiac cycle offer consistent strain assessments, whilst SR measurements gain from further increases in temporal resolution.

Quantification of Myocardial Deformation Applying CMR-Feature-Tracking-All About the Left Ventricle?

PURPOSE OF REVIEW: Cardiac magnetic resonance-feature-tracking (CMR-FT)-based deformation analyses are key tools of cardiovascular imaging and applications in heart failure (HF) diagnostics are expanding. In this review, we outline the current range of application with diagnostic and prognostic implications and provide perspectives on future trends of this technique. RECENT FINDINGS: By applying CMR-FT in different cardiovascular diseases, increasing evidence proves CMR-FT-derived parameters as powerful diagnostic and prognostic imaging biomarkers within the HF continuum partly outperforming traditional clinical values like left ventricular ejection fraction. Importantly, HF diagnostics and deformation analyses by CMR-FT are feasible far beyond sole left ventricular performance evaluation underlining the holistic nature and accuracy of this imaging approach. As an established and continuously evolving technique with strong prognostic implications, CMR-FT deformation analyses enable comprehensive cardiac performance quantification of all cardiac chambers.

Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis.

AIMS: Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes. METHODS AND RESULTS: One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson's trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF-) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF- patients, P = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0-369), P = 0.01]. CONCLUSION: Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

Development of the Commercial Manufacturing Process for Ipatasertib.

Ipatasertib is a potent small molecule Akt kinase inhibitor currently being tested in Phase III clinical trials for the treatment of metastatic castration-resistant prostate cancer and triple negative metastatic breast cancer. In this paper an overview of the development achievements towards the commercial manufacturing process is given. The convergent synthesis consists of ten steps with eight isolated intermediates and utilizes a wide range of chemical techniques and technologies to build-up this complex drug. All three stereocenters are introduced using enzyme or metal catalysis.

[Personalized ischemia diagnostics in chronic coronary syndrome]. / Personalisierte Ischämiediagnostik beim chronischen Koronarsyndrom.

Myocardial ischemia is triggered by a mismatch between the oxygen supply and demand of the myocardial tissue. The most common cause is coronary artery disease; however, not every coronary stenosis is hemodynamically relevant and leads to myocardial ischemia. The guidelines recommend noninvasive ischemia diagnostics prior to invasive treatment in patients with chronic coronary syndrome. Cardiac computed tomography, stress echocardiography, nuclear cardiological procedures (positron emission tomography and single photon emission computed tomography) and cardiac magnetic resonance imaging are the main diagnostic tools for this purpose and are incorporated into the clinical routine. This article provides a review of the indications, the relative advantages and disadvantages of the respective methods and their utilization in routine clinical practice.

Real-time cardiovascular magnetic resonance T1 and extracellular volume fraction mapping for tissue characterisation in aortic stenosis.

BACKGROUND: Myocardial fibrosis is a major determinant of outcome in aortic stenosis (AS). Novel fast real-time (RT) cardiovascular magnetic resonance (CMR) mapping techniques allow comprehensive quantification of fibrosis but have not yet been compared against standard techniques and histology. METHODS: Patients with severe AS underwent CMR before (n = 110) and left ventricular (LV) endomyocardial biopsy (n = 46) at transcatheter aortic valve replacement (TAVR). Midventricular short axis (SAX) native, post-contrast T1 and extracellular volume fraction (ECV) maps were generated using commercially available modified Look-Locker Inversion recovery (MOLLI) (native: 5(3)3, post-contrast: 4(1)3(1)2) and RT single-shot inversion recovery Fast Low-Angle Shot (FLASH) with radial undersampling. Focal late gadolinium enhancement was excluded from T1 and ECV regions of interest. ECV and LV mass were used to calculate LV matrix volumes. Variability and agreements were assessed between RT, MOLLI and histology using intraclass correlation coefficients, coefficients of variation and Bland Altman analyses. RESULTS: RT and MOLLI derived ECV were similar for midventricular SAX slice coverage (26.2 vs. 26.5, p = 0.073) and septal region of interest (26.2 vs. 26.5, p = 0.216). MOLLI native T1 time was in median 20 ms longer compared to RT (p < 0.001). Agreement between RT and MOLLI was best for ECV (ICC > 0.91), excellent for post-contrast T1 times (ICC > 0.81) and good for native T1 times (ICC > 0.62). Diffuse collagen volume fraction by biopsies was in median 7.8%. ECV (RT r = 0.345, p = 0.039; MOLLI r = 0.40, p = 0.010) and LV matrix volumes (RT r = 0.45, p = 0.005; MOLLI r = 0.43, p = 0.007) were the only parameters associated with histology. CONCLUSIONS: RT mapping offers fast and sufficient ECV and LV matrix volume calculation in AS patients. ECV and LV matrix volume represent robust and universally comparable parameters with associations to histologically assessed fibrosis and may emerge as potential targets for clinical decision making.

Left Atrial Function with MRI Enables Prediction of Cardiovascular Events after Myocardial Infarction: Insights from the AIDA STEMI and TATORT NSTEMI Trials.

Background The role of left atrial (LA) performance in acute myocardial infarction (AMI) remains controversial. Cardiac MRI myocardial feature tracking (hereafter, MRI-FT) is a method used to quantify myocardial function that enables reliable assessment of atrial function. Purpose To assess the relationship between LA function assessed with MRI-FT and major adverse cardiovascular events (MACE) after AMI. Materials and Methods This secondary analysis of two prospective multicenter cardiac MRI studies (AIDA STEMI [NCT00712101] and TATORT NSTEMI [NCT01612312]) included 1235 study participants with ST-elevation myocardial infarction (n = 795) or non-ST-elevation myocardial infarction (n = 440) between July 2008 and June 2013. All study participants underwent primary percutaneous coronary intervention. MRI-FT analyses were performed in a core laboratory by researchers blinded to clinical status to determine LA performance using LA reservoir function peak systolic strain (εs), LA conduit strain (εe), and LA booster pump function active strain (εa). The relationship of LA performance to a MACE within 12 months after AMI was evaluated by using Cox proportional hazards models and area under the receiver operating characteristic curve (AUC). Results Study participants with MACE had worse LA performance parameters compared with study participants without MACE (εs = 21.2% vs 16.2%, εe = 8.8% vs 6.9%, εa = 11.8% vs 10%; P < .001 for all). All atrial parameters were strongly associated with MACE (hazard ratio [HR], εs = 0.9, εe = 0.88, εa = 0.89; P < .001 for all). For εs, a cutoff of 18.8% was identified as the only independent atrial parameter with which to predict MACE after accounting for confounders and established prognostic markers in adjusted analysis (HR, 0.95; P = .02). The εs yielded incremental prognostic value above left ventricular ejection fraction, global longitudinal strain, microvascular obstruction, and infarct size (AUC comparisons, P < .04 for all). Conclusion Feature tracking of cardiac MRI to derive left atrial peak reservoir strain provided incremental prognostic value for major adverse cardiovascular events prediction versus established cardiac risk factors after acute myocardial infarction. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Almeida in this issue.

Acute adverse events in cardiac MR imaging with gadolinium-based contrast agents: results from the European Society of Cardiovascular Radiology (ESCR) MRCT Registry in 72,839 patients.

OBJECTIVES: To assess the incidence of acute adverse events (AAEs) in gadolinium-enhanced cardiac magnetic resonance (CMR) imaging. METHODS: Gadolinium-based contrast agent (GBCA)-enhanced CMR data from the multinational, multicenter European Society of Cardiovascular Radiology MRCT Registry was included. AAE severity was classified according to the American College of Radiology Manual on Contrast Media (mild, moderate, severe). Multivariable generalized linear mixed effect models were used to assess the likelihood of AAEs in various GBCA, adjusting for pharmacological stressor, main indications (i.e., suspected or known coronary artery disease or myocarditis), age, sex, and submitting center as a random effect. RESULTS: In the study population of 72,839 GBCA-enhanced CMRs, a total of 260 AAEs were reported (0.36%), with a minority of severe AAEs (n = 24, 0.033%). Allergic-like AAEs were less likely than physiologic AAEs (29% versus 71%). Patients without pharmacological stress imaging had a lower AAE rate (0.22%) compared to stress imaging (0.75%), with the highest AAE rates for regadenoson (2.95%). AAE rates also varied by GBCA subtype (overall p < 0.001). There was significant interaction between GBCA and pharmacological stressor (interaction p = 0.025), with AAE rates ranging between 0 and 10% for certain GBCA/stressor combinations. There was further marginal evidence that higher GBCA volume was associated with higher AAE incidence (OR = 1.02, p = 0.05). CONCLUSION: GBCA-enhanced CMR imaging demonstrates low AAE rates comparable to those of other body regions. AAE likelihood correlates with GBCA subtype, pharmacological stressor, and imaging indication. Intravenous fluid administration in patients with cardiac impairment might contribute to these findings. KEY POINTS: • Acute adverse event rates in cardiac magnetic resonance (CMR) imaging with gadolinium-based contrast agents (GBCAs) are low (0.36%), especially for severe adverse events (0.033%). • Mild and moderate adverse events are more frequent during stress CMR imaging. • Physiologic AAEs are more common than allergic AAEs in CMR imaging.

Fully automated quantification of biventricular volumes and function in cardiovascular magnetic resonance: applicability to clinical routine settings.

BACKGROUND: Cardiovascular magnetic resonance (CMR) represents the clinical gold standard for the assessment of biventricular morphology and function. Since manual post-processing is time-consuming and prone to observer variability, efforts have been directed towards automated volumetric quantification. In this study, we sought to validate the accuracy of a novel approach providing fully automated quantification of biventricular volumes and function in a "real-world" clinical setting. METHODS: Three-hundred CMR examinations were randomly selected from the local data base. Fully automated quantification of left ventricular (LV) mass, LV and right ventricular (RV) end-diastolic and end-systolic volumes (EDV/ESV), stroke volume (SV) and ejection fraction (EF) were performed overnight using commercially available software (suiteHEART®, Neosoft, Pewaukee, Wisconsin, USA). Parameters were compared to manual assessments (QMass®, Medis Medical Imaging Systems, Leiden, Netherlands). Sub-group analyses were further performed according to image quality, scanner field strength, the presence of implanted aortic valves and repaired Tetralogy of Fallot (ToF). RESULTS: Biventricular automated segmentation was feasible in all 300 cases. Overall agreement between fully automated and manually derived LV parameters was good (LV-EF: intra-class correlation coefficient [ICC] 0.95; bias - 2.5% [SD 5.9%]), whilst RV agreement was lower (RV-EF: ICC 0.72; bias 5.8% [SD 9.6%]). Lowest agreement was observed in case of severely altered anatomy, e.g. marked RV dilation but normal LV dimensions in repaired ToF (LV parameters ICC 0.73-0.91; RV parameters ICC 0.41-0.94) and/or reduced image quality (LV parameters ICC 0.86-0.95; RV parameters ICC 0.56-0.91), which was more common on 3.0 T than on 1.5 T. CONCLUSIONS: Fully automated assessments of biventricular morphology and function is robust and accurate in a clinical routine setting with good image quality and can be performed without any user interaction. However, in case of demanding anatomy (e.g. repaired ToF, severe LV hypertrophy) or reduced image quality, quality check and manual re-contouring are still required.

Strain-encoded cardiac magnetic resonance imaging: a new approach for fast estimation of left ventricular function.

BACKGROUND: Recently introduced fast strain-encoded (SENC) cardiac magnetic resonance (CMR) imaging (fast-SENC) provides real-time acquisition of myocardial performance in a single heartbeat. We aimed to test the ability and accuracy of real-time strain-encoded CMR imaging to estimate left ventricular volumes, ejection fraction and mass. METHODS: Thirty-five subjects (12 healthy volunteers and 23 patients with known or suspected coronary artery disease) were investigated. All study participants were imaged at 1.5 Tesla MRI scanner (Achieva, Philips) using an advanced CMR study protocol which included conventional cine and fast-SENC imaging. A newly developed real-time free-breathing SENC imaging technique based on the acquisition of two images with different frequency modulation was employed. RESULTS: All parameters were successfully derived from fast-SENC images with total study time of 105 s (a 15 s scan time and a 90 s post-processing time). There was no significant difference between fast-SENC and cine imaging in the estimation of LV volumes and EF, whereas fast-SENC underestimated LV end-diastolic mass by 7%. CONCLUSION: The single heartbeat fast-SENC technique can be used as a good alternative to cine imaging for the precise calculation of LV volumes and ejection fraction while the technique significantly underestimates LV end-diastolic mass.