Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion.

Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing. In healthy pigs an intravenous ATTM dose escalation revealed a reproducible pharmacokinetic/pharmacodynamic (PK/PD) relationship with minimal adverse clinical or biochemical events. In a myocardial infarction (1-h occlusion of the left anterior descending coronary artery)-reperfusion model, intravenous ATTM or saline was commenced just prior to reperfusion. ATTM protected the heart (24-h histological examination) in a drug-exposure-dependent manner (r2 = 0.58, p < 0.05). Blood troponin T levels were significantly (p < 0.05) lower in ATTM-treated animals while myocardial glutathione peroxidase activity, an antioxidant selenoprotein, was elevated (p < 0.05). Overall, our study represents a significant advance in the development of sulfides as therapeutics and underlines the potential of ATTM as a novel adjunct therapy for reperfusion injury. Mechanistically, our study suggests that modulating selenoprotein activity could represent an additional mode of action of sulfide-releasing drugs.

CMR reclassifies the majority of patients with suspected MINOCA and non MINOCA.

AIMS: In ∼5-15% of all cases of acute coronary syndromes (ACS) have unobstructed coronaries on angiography. Cardiac magnetic resonance (CMR) has proven useful to identify in most patients the underlying diagnosis associated with this presentation. However, the role of CMR to reclassify patients from the initial suspected condition has not been clarified. The aim of this study was to assess the proportion of patients with suspected MINOCA, or non-MINOCA, that CMR reclassifies with an alternative diagnosis from the original clinical suspicion. METHODS AND RESULTS: A retrospective cohort of patients in a tertiary cardiology centre was identified from a registry database. Patients who were referred for CMR for investigation of suspected MINOCA, and a diagnosis pre- and post-CMR was recorded to determine the proportion of diagnoses reclassified. A total of 888 patients were identified in the registry. CMR reclassified diagnosis in 78% of patients. Diagnosis of MINOCA was confirmed in only 243 patients (27%), whilst most patients had an alternative diagnosis (73%): myocarditis n = 217 (24%), Takotsubo syndrome n = 115 (13%), cardiomyopathies n = 97 (11%), and normal CMR/non-specific n = 216 (24%). CONCLUSION: In a large single-centre cohort of patients presenting with ACS and unobstructed coronary arteries, most patients had a non-MINOCA diagnosis (73%) (myocarditis, Takotsubo, cardiomyopathies, or normal CMR/non-specific findings), whilst only a minority had confirmed MINOCA (27%). Performing CMR led to reclassifying patients' diagnosis in 78% of cases, thus confirming its important clinical role and underscoring the clinical challenge in diagnosing MINOCA and non MINOCA conditions.

MRI-based strain measurements reflect morphological changes following myocardial infarction: A study on the UK Biobank cohort.

In a porcine experimental model of myocardial infarction, a localised, layer-specific, circumferential left ventricular strain metric has been shown to indicate chronic changes in ventricular function post-infarction more strongly than ejection fraction. This novel strain metric might therefore provide useful prognostic information clinically. In this study, existing clinical volume indices, global strains, and the novel, layer-specific strain were calculated for a large human cohort to assess variations in ventricular function and morphology with age, sex, and health status. Imaging and health data from the UK Biobank were obtained, including healthy volunteers and those with a history of cardiovascular illness. In total, 710 individuals were analysed and stratified by age, sex and health. Significant differences in all strain metrics were found between healthy and unhealthy populations, as well as between males and females. Significant differences in basal circumferential strain and global circumferential strain were found between healthy males and females, with males having smaller absolute values for both (all p ≤ 0.001). There were significant differences in the functional variables left ventricular ejection fraction, end-systolic volume, end-systolic volume index and mid-ventricular circumferential strain between healthy and unhealthy male cohorts aged 65-74 (all p ≤ 0.001). These results suggest that whilst regional circumferential strains may be useful clinically for assessing cardiovascular health, care must be taken to ensure critical values are indexed correctly to age and sex, due to the differences in these values observed here.

Altered Aortic Hemodynamics and Relative Pressure in Patients with Dilated Cardiomyopathy.

Ventricular-vascular interaction is central in the adaptation to cardiovascular disease. However, cardiomyopathy patients are predominantly monitored using cardiac biomarkers. The aim of this study is therefore to explore aortic function in dilated cardiomyopathy (DCM). Fourteen idiopathic DCM patients and 16 controls underwent cardiac magnetic resonance imaging, with aortic relative pressure derived using physics-based image processing and a virtual cohort utilized to assess the impact of cardiovascular properties on aortic behaviour. Subjects with reduced left ventricular systolic function had significantly reduced aortic relative pressure, increased aortic stiffness, and significantly delayed time-to-pressure peak duration. From the virtual cohort, aortic stiffness and aortic volumetric size were identified as key determinants of aortic relative pressure. As such, this study shows how advanced flow imaging and aortic hemodynamic evaluation could provide novel insights into the manifestation of DCM, with signs of both altered aortic structure and function derived in DCM using our proposed imaging protocol.

Myocardial inflammation and energetics by cardiac MRI: a review of emerging techniques.

The role of inflammation in cardiovascular pathophysiology has gained a lot of research interest in recent years. Cardiovascular Magnetic Resonance has been a powerful tool in the non-invasive assessment of inflammation in several conditions. More recently, Ultrasmall superparamagnetic particles of iron oxide have been successfully used to evaluate macrophage activity and subsequently inflammation on a cellular level. Current evidence from research studies provides encouraging data and confirms that this evolving method can potentially have a huge impact on clinical practice as it can be used in the diagnosis and management of very common conditions such as coronary artery disease, ischaemic and non-ischaemic cardiomyopathy, myocarditis and atherosclerosis. Another important emerging concept is that of myocardial energetics. With the use of phosphorus magnetic resonance spectroscopy, myocardial energetic compromise has been proved to be an important feature in the pathophysiological process of several conditions including diabetic cardiomyopathy, inherited cardiomyopathies, valvular heart disease and cardiac transplant rejection. This unique tool is therefore being utilized to assess metabolic alterations in a wide range of cardiovascular diseases. This review systematically examines these state-of-the-art methods in detail and provides an insight into the mechanisms of action and the clinical implications of their use.

Late unexpected complete fracture of a right ventricular lead still capturing the myocardium.

A 72-year-old man presented for routine dual chamber pacemaker interrogation 13 years following insertion for sick sinus syndrome. Increased noise, impedance and threshold of the right ventricular (RV) lead were identified. RV capture was maintained with an overall RV pacing burden of 47%. A routine generator replacement was scheduled alongside RV lead replacement. Fluoroscopy at the start of the procedure revealed an unexpected striking fracture of the RV pacing lead with complete separation of the proximal and distal portions within the RV. The patient was asymptomatic and described no predisposing factors. He underwent implantation of a new ventricular lead and generator and has remained well. This case demonstrates clear RV lead fracture as a late complication of pacemaker implantation despite maintained capture. This emphasises the need for a chest X-ray when a change in device parameters is noted at device interrogation even in the absence of symptoms.

Clinical Translation of Three-Dimensional Scar, Diffusion Tensor Imaging, Four-Dimensional Flow, and Quantitative Perfusion in Cardiac MRI: A Comprehensive Review.

Cardiovascular magnetic resonance (CMR) imaging is a versatile tool that has established itself as the reference method for functional assessment and tissue characterisation. CMR helps to diagnose, monitor disease course and sub-phenotype disease states. Several emerging CMR methods have the potential to offer a personalised medicine approach to treatment. CMR tissue characterisation is used to assess myocardial oedema, inflammation or thrombus in various disease conditions. CMR derived scar maps have the potential to inform ablation therapy-both in atrial and ventricular arrhythmias. Quantitative CMR is pushing boundaries with motion corrections in tissue characterisation and first-pass perfusion. Advanced tissue characterisation by imaging the myocardial fibre orientation using diffusion tensor imaging (DTI), has also demonstrated novel insights in patients with cardiomyopathies. Enhanced flow assessment using four-dimensional flow (4D flow) CMR, where time is the fourth dimension, allows quantification of transvalvular flow to a high degree of accuracy for all four-valves within the same cardiac cycle. This review discusses these emerging methods and others in detail and gives the reader a foresight of how CMR will evolve into a powerful clinical tool in offering a precision medicine approach to treatment, diagnosis, and detection of disease.

Influence of the arterial input sampling location on the diagnostic accuracy of cardiovascular magnetic resonance stress myocardial perfusion quantification.

BACKGROUND: Quantification of myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) by cardiovascular magnetic resonance (CMR) perfusion requires sampling of the arterial input function (AIF). While variation in the AIF sampling location is known to impact quantification by CMR and positron emission tomography (PET) perfusion, there is no evidence to support the use of a specific location based on their diagnostic accuracy in the detection of coronary artery disease (CAD). This study aimed to evaluate the accuracy of stress MBF and MPR for different AIF sampling locations for the detection of abnormal myocardial perfusion with expert visual assessment as the reference. METHODS: Twenty-five patients with suspected or known CAD underwent vasodilator stress-rest perfusion with a dual-sequence technique at 3T. A low-resolution slice was acquired in 3-chamber view to allow AIF sampling at five different locations: left atrium (LA), basal left ventricle (bLV), mid left ventricle (mLV), apical left ventricle (aLV) and aortic root (AoR). MBF and MPR were estimated at the segmental level using Fermi function-constrained deconvolution. Segments were scored as having normal or abnormal perfusion by visual assessment and the diagnostic accuracy of stress MBF and MPR for each location was evaluated using receiver operating characteristic curve analysis. RESULTS: In both normal (300 out of 400, 75 %) and abnormal segments, rest MBF, stress MBF and MPR were significantly different across AIF sampling locations (p < 0.001). Stress MBF for the AoR (normal: 2.42 (2.15-2.84) mL/g/min; abnormal: 1.71 (1.28-1.98) mL/g/min) had the highest diagnostic accuracy (sensitivity 80 %, specificity 85 %, area under the curve 0.90; p < 0.001 versus stress MBF for all other locations including bLV: normal: 2.78 (2.39-3.14) mL/g/min; abnormal: 2.22 (1.83-2.48) mL/g/min; sensitivity 91 %, specificity 63 %, area under the curve 0.81) and performed better than MPR for the LV locations (p < 0.01). MPR for the AoR (normal: 2.43 (1.95-3.14); abnormal: 1.58 (1.34-1.90)) was not superior to MPR for the bLV (normal: 2.59 (2.04-3.20); abnormal: 1.69 (1.36-2.14); p = 0.717). CONCLUSIONS: The AIF sampling location has a significant impact on MBF and MPR estimates by CMR perfusion, with AoR-based stress MBF comparing favorably to that for the current clinical reference bLV.

Importance of thorough investigation in a patient presenting with recurrent collapse and ST elevation.

There is increasing literature to suggest numerous subgroups of Brugada syndrome (BrS), including those with ST elevation in the lateral or inferior leads. We present a case of a patient presenting with recurrent collapse and inferior ST elevation degenerating to ventricular fibrillation and ultimately leading to a diagnosis of BrS.

Impact of COVID-19 on inpatient referral of acute heart failure: a single-centre experience from the south-west of the UK.

AIMS: Healthcare services worldwide have been significantly impacted by the COVID-19 pandemic. Recent reports have shown a decline in hospitalization for emergency cardiac conditions. The impact of the COVID-19 pandemic on hospitalization and particularly mortality due to acute heart failure has not been thoroughly described. METHODS AND RESULTS: In this single-centre observational study, we examined referrals to the acute heart failure team over a period of 16 weeks (7 January to 27 April 2020) spanning the ongoing COVID-19 pandemic; 283 patients referred to our acute heart failure services over the study period were included on the basis of typical symptoms, raised BNP, and echocardiogram. There was a substantial but statistically non-significant drop in referrals with 164 referred in the 8 weeks before the first UK death due to COVID-19 on 2 March 2020 (BC), compared with 119 referred after (AC) in the subsequent 8 weeks, representing a 27% reduction overall (P = 0.06). The 30 day case fatality rate was increased from 11% in the BC group compared with 21% in the AC group (risk ratio = 1.9, 95% confidence interval 1.09-3.3). Age, gender, length of stay, left ventricular ejection fraction, and N-terminal pro-brain natriuretic peptide were similar between the groups. Admission creatinine, age, and AC cohort status were found to be univariable predictors of mortality. On multivariate Cox regression analysis, only age (hazard ratio 1.04, P = 0.03) and AC cohort status (hazard ratio 2.1, P = 0.017) remained significant predictors of mortality. On sensitivity analysis, this increased mortality was driven by COVID-19 positive status. CONCLUSIONS: There was a reduction in referral of patients with acute heart failure with significant increase in mortality in the 8 weeks following the first reported UK death due to COVID-19. The observation of increased mortality does not appear related to a change in population in terms of demographics, left ventricular ejection fraction, or N-terminal pro-brain natriuretic peptide. The observed increased mortality appears to be related to the coexistence of COVID19 infection with acute heart failure. The study highlights the need for widespread preventative and shielding measures particularly in this group of patients especially in the light of the second wave. Longer follow-up with inclusion of data from other centres and community heart failure services will be needed.

Quantitative evaluation and comparison of coronary artery characteristics by 3D coronary volume reconstruction.

Non-atherosclerotic abnormalities of vessel calibre, aneurysm and ectasia, are challenging to quantify and are often overlooked in qualitative reporting. Utilising a novel 3-dimensional (3D) quantitative coronary angiography (QCA) application, we have evaluated the characteristics of normal, diabetic and aneurysmal or ectatic coronary arteries. We selected 131 individuals under 50 years-of-age, who had undergone coronary angiography for suspected myocardial ischaemia between 1st January 2011 and 31st December 2015, at the Bristol Heart Institute, Bristol, UK. This included 42 patients with angiographically normal coronary arteries, 36 diabetic patients with unobstructed coronaries, and 53 patients with abnormal coronary dilatation (aneurysm and ectasia). A total of 1105 coronary segments were analysed using QAngio XA 3D (Research Edition, Medis medical imaging systems, Leiden, The Netherlands). The combined volume of the major coronary arteries was significantly different between each group (1240 ± 476 mm3 diabetic group, 1646 ± 391 mm3 normal group, and 2072 ± 687 mm3 abnormal group). Moreover, the combined coronary artery volumes correlated with patient body surface area (r = 0.483, p < 0.01). Inter-observer variability was assessed and intraclass correlation coefficient of the total coronary artery volume demonstrated a low variability of 3D QCA (r = 0.996, p < 0.001). Dedicated 3D QCA facilitates reproducible coronary artery volume estimation and allows discrimination of normal and diseased vessels.

Comparison of the within-reader and inter-vendor agreement of left ventricular circumferential strains and volume indices derived from cardiovascular magnetic resonance imaging.

PURPOSE: Volume indices and left ventricular ejection fraction (LVEF) are routinely used to assess cardiac function. Ventricular strain values may provide additional diagnostic information, but their reproducibility is unclear. This study therefore compares the repeatability and reproducibility of volumes, volume fraction, and regional ventricular strains, derived from cardiovascular magnetic resonance (CMR) imaging, across three software packages and between readers. METHODS: Seven readers analysed 16 short-axis CMR stacks of a porcine heart. Endocardial contours were manually drawn using OsiriX and Simpleware ScanIP and repeated in both softwares. The images were also contoured automatically in Circle CVI42. Endocardial global, apical, mid-ventricular, and basal circumferential strains, as well as end-diastolic and end-systolic volume and LVEF were compared. RESULTS: Bland-Altman analysis found systematic biases in contour length between software packages. Compared to OsiriX, contour lengths were shorter in both ScanIP (-1.9 cm) and CVI42 (-0.6 cm), causing statistically significant differences in end-diastolic and end-systolic volumes, and apical circumferential strain (all p<0.006). No differences were found for mid-ventricular, basal or global strains, or left ventricular ejection fraction (all p<0.007). All CVI42 results lay within the ranges of the OsiriX results. Intra-software differences were found to be lower than inter-software differences. CONCLUSION: OsiriX and CVI42 gave consistent results for all strain and volume metrics, with no statistical differences found between OsiriX and ScanIP for mid-ventricular, global or basal strains, or left ventricular ejection fraction. However, volumes were influenced by the choice of contouring software, suggesting care should be taken when comparing volumes across different software.

Deep-Learning-Based Preprocessing for Quantitative Myocardial Perfusion MRI.

BACKGROUND: Quantitative myocardial perfusion cardiac MRI can provide a fast and robust assessment of myocardial perfusion status for the noninvasive diagnosis of myocardial ischemia while being more objective than visual assessment. However, it currently has limited use in clinical practice due to the challenging postprocessing required, particularly the segmentation. PURPOSE: To evaluate the efficacy of an automated deep learning (DL) pipeline for image processing prior to quantitative analysis. STUDY TYPE: Retrospective. POPULATION: In all, 175 (350 MRI scans; 1050 image series) clinical patients under both rest and stress conditions (135/10/30 training/validation/test). FIELD STRENGTH/SEQUENCE: 3.0T/2D multislice saturation recovery T1 -weighted gradient echo sequence. ASSESSMENT: Accuracy was assessed, as compared to the manual operator, through the mean square error of the distance between landmarks and the Dice similarity coefficient of the segmentation and bounding box detection. Quantitative perfusion maps obtained using the automated DL-based processing were compared to the results obtained with the manually processed images. STATISTICAL TESTS: Bland-Altman plots and intraclass correlation coefficient (ICC) were used to assess the myocardial blood flow (MBF) obtained using the automated DL pipeline, as compared to values obtained by a manual operator. RESULTS: The mean (SD) error in the detection of the time of peak signal enhancement in the left ventricle was 1.49 (1.4) timeframes. The mean (SD) Dice similarity coefficients for the bounding box and myocardial segmentation were 0.93 (0.03) and 0.80 (0.06), respectively. The mean (SD) error in the RV insertion point was 2.8 (1.8) mm. The Bland-Altman plots showed a bias of 2.6% of the mean MBF between the automated and manually processed MBF values on a per-myocardial segment basis. The ICC was 0.89, 95% confidence interval = [0.87, 0.90]. DATA CONCLUSION: We showed high accuracy, compared to manual processing, for the DL-based processing of myocardial perfusion data leading to quantitative values that are similar to those achieved with manual processing. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2020;51:1689-1696.

The interaction of QRS duration with cardiac magnetic resonance derived scar and mechanical dyssynchrony in systolic heart failure: Implications for cardiac resynchronization therapy.

BACKGROUND: Trials using echocardiographic mechanical dyssynchrony (MD) parameters in narrow QRS patients have shown a negative response to CRT. We hypothesized MD in these patients may relate to myocardial scar rather than electrical dyssynchrony. METHODS: We determined the prevalence of cardiac magnetic resonance (CMR) derived measures of MD in 130 systolic heart failure patients with both broad (≥ 130 ms - BQRS) and narrow QRS duration (< 130 ms - NQRS). We assessed whether late gadolinium enhancement derived scar might explain the presence of MD amongst narrow QRS patients. Dyssynchrony was calculated on the basis of a systolic dyssynchrony index (SDI). RESULTS: Fifty-nine patients (45%) had a NQRS and the remaining had QRS ≥ 130 ms (BQRS group). 25% of NQRS patients had MD based on SDI. In all narrow and broad QRS patients with MD there was a significantly lower scar volume than those without MD (7.4 ± 10.5% vs 13.7 ± 13.3% vs. p < 0.01). This was the case in the BQRS group with a significantly lower scar burden in patients with MD (5.0 ± 7.7% vs 15.4 ± 15.6%, p < 0.01). Notably in the NQRS group this difference was absent with an equal scar burden in patients with MD 13.3 ± 13.9% and without MD 12.5 ± 11%, p = 0.92. CONCLUSIONS: 25% of patients with systolic heart failure and a NQRS (< 130 ms) have CMR derived mechanical dyssynchrony. Our findings suggest MD in this group may be secondary to myocardial scar rather than electrical dyssynchrony and therefore not amenable to correction by CRT. This may give insight into non-response and potential harm from CRT in this group.

Exploring kinetic energy as a new marker of cardiac function in the single ventricle circulation.

Ventricular volumetric ejection fraction (VV EF) is often normal in patients with single ventricle circulations despite them experiencing symptoms related to circulatory failure. We sought to determine if kinetic energy (KE) could be a better marker of ventricular performance. KE was prospectively quantified using four-dimensional flow MRI in 41 patients with a single ventricle circulation (aged 0.5-28 yr) and compared with 43 healthy volunteers (aged 1.5-62 yr) and 14 patients with left ventricular (LV) dysfunction (aged 28-79 yr). Intraventricular end-diastolic blood was tracked through systole and divided into ejected and residual blood components. Two ejection fraction (EF) metrics were devised based on the KE of the ejected component over the total of both the ejected and residual components using 1) instantaneous peak KE to assess KE EF or 2) summating individual peak particle energy (PE) to assess PE EF. KE EF and PE EF had a smaller range than VV EF in healthy subjects (97.9 ± 0.8 vs. 97.3 ± 0.8 vs. 60.1 ± 5.2%). LV dysfunction caused a fall in KE EF ( P = 0.01) and PE EF ( P = 0.0001). VV EF in healthy LVs and single ventricle hearts was equivalent; however, KE EF and PE EF were lower ( P < 0.001) with a wider range indicating a spectrum of severity. Those reporting the greatest symptomatic impairment (New York Heart Association II) had lower PE EF than asymptomatic subjects ( P = 0.0067). KE metrics are markers of healthy cardiac function. PE EF may be useful in grading dysfunction. NEW & NOTEWORTHY Kinetic energy (KE) represents the useful work of the heart in ejecting blood. This article details the utilization of KE indexes to assess cardiac function in health and a variety of pathophysiological conditions. KE ejection fraction and particle energy ejection fraction (PE EF) showed a narrow range in health and a lower wider range in disease representing a spectrum of severity. PE EF was altered by functional status potentially offering the opportunity to grade dysfunction.