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Metformin is an antihyperglycemic used to treat type 2 diabetes mellitus (T2DM). Patients with T2DM are at increased risk of cardiovascular disease. We explored the association between metformin use and cardiovascular magnetic resonance (CMR) derived stress myocardial blood flow (MBF), myocardial perfusion reserve (MPR) and major adverse cardiovascular events (MACE; all cause death, MI, stroke, heart failure hospitalisation and coronary revascularisation) in patients with T2DM. Multi-centre study of patients with T2DM, and healthy controls, underwent quantitative myocardial perfusion CMR using an artificial intelligence supported process. Multivariable regression analysis, and cox proportional hazard models of propensity score weighted patients quantified associations between metformin use, MBF, MPR, all cause death and MACE. Analysis included 572 patients with T2DM (68% prescribed metformin) with median follow-up 851 days (IQR 935 − 765). Metformin use was associated with an increase of MPR of 0.12 [0.08–0.40], p  = 0.004. There were 82 MACE events (14.3%) including 25 (4.4%) deaths of which 16 were in those not prescribed metformin (8.7%), compared to 9 in patients prescribed metformin (2.3%): adjusted hazard ratio 0.24 (95% CI 0.08–0.70, p  = 0.009). MACE events were similar between groups. This multicentre, inverse probability weighting propensity score analysis study showed that in patients with T2DM, metformin use is associated with higher MPR and improved all cause survival.

Background Adenosine stress perfusion cardiovascular magnetic resonance (CMR) is commonly used in the assessment of patients with suspected ischaemia. Accepted protocols recommend administration of adenosine at a dose of 140 µg/kg/min increased up to 210 µg/kg/min if required. Conventionally, adequate stress has been assessed using change in heart rate, however, recent studies have suggested that these peripheral measurements may not reflect hyperaemia and can be blunted, in particular, in patients with heart failure. This study looked to compare stress myocardial blood flow (MBF) and haemodynamic response with different dosing regimens of adenosine during stress perfusion CMR in patients and healthy controls. Methods 20 healthy adult subjects were recruited as controls to compare 3 adenosine perfusion protocols: standard dose (140 µg/kg/min for 4 min), high dose (210 µg/kg/min for 4 min) and long dose (140 µg/kg/min for 8 min). 60 patients with either known or suspected coronary artery disease (CAD) or with heart failure and different degrees of left ventricular (LV) dysfunction underwent adenosine stress with standard and high dose adenosine within the same scan. All studies were carried out on a 3 T CMR scanner. Quantitative global myocardial perfusion and haemodynamic response were compared between doses. Results In healthy controls, no significant difference was seen in stress MBF between the 3 protocols. In patients with known or suspected CAD, and those with heart failure and mild systolic impairment (LV ejection fraction (LVEF) ≥ 40%) no significant difference was seen in stress MBF between standard and high dose adenosine. In those with LVEF < 40%, there was a significantly higher stress MBF following high dose adenosine compared to standard dose (1.33 ± 0.46 vs 1.10 ± 0.47 ml/g/min, p = 0.004). Non-responders to standard dose adenosine (defined by an increase in heart rate (HR) < 10 bpm) had a significantly higher stress HR following high dose (75 ± 12 vs 70 ± 14 bpm, p = 0.034), but showed no significant difference in stress MBF. Conclusions Increasing adenosine dose from 140 to 210 µg/kg/min leads to increased stress MBF in patients with significantly impaired LV systolic function. Adenosine dose in clinical perfusion assessment may need to be increased in these patients.

Background Quantitative myocardial perfusion mapping using cardiovascular magnetic resonance (CMR) is validated for myocardial blood flow (MBF) estimation in native vessel coronary artery disease (CAD). Following coronary artery bypass graft (CABG) surgery, perfusion defects are often detected in territories supplied by the left internal mammary artery (LIMA) graft, but their interpretation and subsequent clinical management is variable. Methods We assessed myocardial perfusion using quantitative CMR perfusion mapping in 38 patients with prior CABG surgery, all with angiographically-proven patent LIMA grafts to the left anterior descending coronary artery (LAD) and no prior infarction in the LAD territory. Factors potentially determining MBF in the LIMA–LAD myocardial territory, including the impact of delayed contrast arrival through the LIMA graft were evaluated. Results Perfusion defects were reported on blinded visual analysis in the LIMA–LAD territory in 27 (71%) cases, despite LIMA graft patency and no LAD infarction. Native LAD chronic total occlusion (CTO) was a strong independent predictor of stress MBF (B = − 0.41, p = 0.014) and myocardial perfusion reserve (MPR) (B = − 0.56, p = 0.005), and was associated with reduced stress MBF in the basal (1.47 vs 2.07 ml/g/min; p = 0.002) but not the apical myocardial segments (1.52 vs 1.87 ml/g/min; p = 0.057). Extending the maximum arterial time delay incorporated in the quantitative perfusion algorithm, resulted only in a small increase (3.4%) of estimated stress MBF. Conclusions Perfusion defects are frequently detected in LIMA–LAD subtended territories post CABG despite LIMA patency. Although delayed contrast arrival through LIMA grafts causes a small underestimation of MBF, perfusion defects are likely to reflect true reductions in myocardial blood flow, largely due to proximal native LAD disease.

Background To assess the feasibility of biventricular SAPPHIRE T 1 mapping in vivo across field strengths using diastolic, systolic and dark-blood (DB) approaches. Methods 10 healthy volunteers underwent same-day non-contrast cardiovascular magnetic resonance at 1.5 Tesla (T) and 3 T. Left and right ventricular (LV, RV) T 1 mapping was performed in the basal, mid and apical short axis using 4-variants of SAPPHIRE: diastolic, systolic, 0th and 2nd order motion-sensitized DB and conventional modified Look-Locker inversion recovery (MOLLI). Results LV global myocardial T 1 times (1.5 T then 3 T results) were significantly longer by diastolic SAPPHIRE (1283 ± 11|1600 ± 17 ms) than any of the other SAPPHIRE variants: systolic (1239 ± 9|1595 ± 13 ms), 0th order DB (1241 ± 10|1596 ± 12) and 2nd order DB (1251 ± 11|1560 ± 20 ms, all p  < 0.05). In the mid septum MOLLI and diastolic SAPPHIRE exhibited significant T 1 signal contamination (longer T 1 ) at the blood-myocardial interface not seen with the other 3 SAPPHIRE variants (all p  < 0.025). Additionally, systolic, 0th order and 2nd order DB SAPPHIRE showed narrower dispersion of myocardial T 1 times across the mid septum when compared to diastolic SAPPHIRE (interquartile ranges respectively: 25 ms, 71 ms, 73 ms vs 143 ms, all p  < 0.05). RV T 1 mapping was achievable using systolic, 0th and 2nd order DB SAPPHIRE but not with MOLLI or diastolic SAPPHIRE. All 4 SAPPHIRE variants showed excellent re-read reproducibility (intraclass correlation coefficients 0.953 to 0.996). Conclusion These small-scale preliminary healthy volunteer data suggest that DB SAPPHIRE has the potential to reduce partial volume effects at the blood-myocardial interface, and that systolic SAPPHIRE could be a feasible solution for right ventricular T 1 mapping. Further work is needed to understand the robustness of these sequences and their potential clinical utility.

Coronary artery bypass graft (CABG) surgery effectively relieves symptoms and improves outcomes. However, patients undergoing CABG surgery typically have advanced coronary atherosclerotic disease and remain at high risk for symptom recurrence and adverse events. Functional non-invasive testing for ischaemia is commonly used as a gatekeeper for invasive coronary and graft angiography, and for guiding subsequent revascularisation decisions. However, performing and interpreting non-invasive ischaemia testing in patients post CABG is challenging, irrespective of the imaging modality used. Multiple factors including advanced multi-vessel native vessel disease, variability in coronary hemodynamics post-surgery, differences in graft lengths and vasomotor properties, and complex myocardial scar morphology are only some of the pathophysiological mechanisms that complicate ischaemia evaluation in this patient population. Systematic assessment of the impact of these challenges in relation to each imaging modality may help optimize diagnostic test selection by incorporating clinical information and individual patient characteristics. At the same time, recent technological advances in cardiac imaging including improvements in image quality, wider availability of quantitative techniques for measuring myocardial blood flow and the introduction of artificial intelligence-based approaches for image analysis offer the opportunity to re-evaluate the value of ischaemia testing, providing new insights into the pathophysiological processes that determine outcomes in this patient population.

Background: Measurement of myocardial T1 is increasingly incorporated into standard cardiovascular magnetic resonance (CMR) protocols, however accuracy may be reduced in patients with metallic cardiovascular implants. Measurement is feasible in segments free from visual artifact, but there may still be off-resonance induced error. Aim: To quantify off-resonance induced T1 error in patients with metallic cardiovascular implants, and validate a method for error correction for a conventional MOLLI pulse sequence. Methods: Twenty-four patients with cardiac implantable electronic devices (CIEDs: 46% permanent pacemakers, PPMs; 33% implantable loop recorders, ILRs; and 21% implantable cardioverter-defibrillators, ICDs); and 31 patients with aortic valve replacement (AVR) (45% metallic) were studied. Paired mid-myocardial short-axis MOLLI and single breath-hold off-resonance field maps were acquired at 1.5 T. T1 values were measured by AHA segment, and segments with visual artifact were excluded. T1 correction was applied using a published relationship between off-resonance and T1. The accuracy of the correction was assessed in 10 healthy volunteers by measuring T1 before and after external placement of an ICD generator next to the chest to generate off-resonance. Results: T1 values in healthy volunteers with an ICD were underestimated compared to without (967 ± 52 vs. 997 ± 26 ms respectively, p = 0.0001), but were similar after correction ( p = 0.57, residual difference 2 ± 27 ms). Artifact was visible in 4 ± 12, 42 ± 31, and 53 ± 27% of AHA segments in patients with ILRs, PPMs, and ICDs, respectively. In segments without artifact, T1 was underestimated by 63 ms (interquartile range: 7–143) per patient. The greatest error for patients with ILRs, PPMs and ICDs were 79, 146, and 191 ms, respectively. The presence of an AVR did not generate T1 error. Conclusion: Even when there is no visual artifact, there is error in T1 in patients with CIEDs, but not AVRs. Off-resonance field map acquisition can detect error in measured T1, and a correction can be applied to quantify T1 MOLLI accurately.

ObjectiveIn patients with hypertrophic cardiomyopathy (HCM), the role of small vessel disease and myocardial perfusion remains incompletely understood and data on absolute myocardial blood flow (MBF, mL/g/min) are scarce. We measured MBF using cardiovascular magnetic resonance fully quantitative perfusion mapping to determine the relationship between perfusion, hypertrophy and late gadolinium enhancement (LGE) in HCM.Methods101 patients with HCM with unobstructed epicardial coronary arteries and 30 controls (with matched cardiovascular risk factors) underwent pixel-wise perfusion mapping during adenosine stress and rest. Stress, rest MBF and the myocardial perfusion reserve (MPR, ratio of stress to rest) were calculated globally and segmentally and then associated with segmental wall thickness and LGE.ResultsIn HCM, 79% had a perfusion defect on clinical read. Stress MBF and MPR were reduced compared with controls (mean±SD 1.63±0.60 vs 2.30±0.64 mL/g/min, p<0.0001 and 2.21±0.87 vs 2.90±0.90, p=0.0003, respectively). Globally, stress MBF fell with increasing indexed left ventricle mass (R2 for the model 0.186, p=0.036) and segmentally with increasing wall thickness and LGE (both p<0.0001). In 21% of patients with HCM, MBF was lower during stress than rest (MPR <1) in at least one myocardial segment, a phenomenon which was predominantly subendocardial. Apparently normal HCM segments (normal wall thickness, no LGE) had reduced stress MBF and MPR compared with controls (mean±SD 1.88±0.81 mL/g/min vs 2.32±0.78 mL/g/min, p<0.0001).ConclusionsMicrovascular dysfunction is common in HCM and associated with hypertrophy and LGE. Perfusion can fall during vasodilator stress and is abnormal even in apparently normal myocardium suggesting it may be an early disease marker.

IntroductionCardiovascular Magnetic Resonance (CMR) is a highly versatile imaging modality, indicated in the assessment of most common cardiac presentations and is the gold standard for the assessment of cardiac chamber volume, tissue characterisation and myocardial perfusion.In this single UK tertiary centre study, we evaluated inpatient CMR referrals to investigate the impact on patient management.Materials and MethodsPatients who had an inpatient CMR between June to December 2021 were identified. Data collected included patient demographics, indication for CMR, CMR findings and whether patient management changed following the result.ResultsThere were 169 patients included within the study period. 66% were male. The mean age was 57.1 years. Primary indications for CMR included assessment of cardiomyopathies (53% patients), myocardial viability (17%) and suspected coronary artery disease (12%).Inpatient CMR led to an additional or complete change in diagnosis in 29% patients. The commonest diagnosis post-CMR was ischaemic heart disease (infarction/ischaemic cardiomyopathy, 34%). Non-ischaemic LV dysfunction was found in 23% scans, cardiomyopathy (including HCM, infiltrative cardiomyopathies) was detected in 12% and myocarditis was diagnosed in 11%.DiscussionThis is the first study evaluating the use of inpatient CMR in the acute setting and the consequent impact on management at a tertiary centre. CMR changed patient management in 77% cases. This included medication changes, prompting further inpatient diagnostic tests or procedures (e.g.CRT/ICD) or hospital discharge. Interestingly in 6 cases, invasive coronary angiography was not performed due to the CMR result.Image quality was diagnostic (good or adequate) in 93% cine scans and in 87% of scans with late gadolinium enhancement (LGE). Overall CMR was well tolerated in 98% patients; there was one case of contrast extravasation.ConclusionIn this single, UK tertiary centre study we found that CMR impacted upon clinical management 77% of the time. CMR has become a vital tool in the management of cardiology inpatients particularly in the assessment of ischaemic heart disease, heart failure, cardiomyopathy and myocarditis.

IntroductionCardiac MRI is a vital tool in the assessment of heart failure. We investigated the utility of CMR on inpatients admitted to our dedicated heart failure unit (HFU, the first in the UK).Materials and MethodsPatients admitted to our HFU and referred for inpatient CMR from August 2018 – August 2022 were included. Data was collected retrospectively from the electronic patient records including patient demographics, co-morbidities, CMR findings and subsequent major adverse cardiovascular events (MACE).Results85 patients were included, 64 (75%) male, mean age 69(±13)years, 26% had an existing diagnosis of heart failure. The primary reason for admission was decompensated heart failure in 80% patients. There were 66 (78%) patients with HFrEF (EF <40%), 7 (8%) with HFmrEF (EF 40–50%) and 12 (14%) with HFpEF (EF >50%). The indication for CMR was to assess the aetiology of heart failure in 48 (56%) patients. 65 (76%) patients had an invasive coronary angiogram during their acute admission.CMR was performed in 78 patients, 6 did not tolerate the scan and late gadolinium enhancement was non-diagnostic in 1 patient. The aetiology of heart failure was ischaemic in 24 (31%) patients and non-ischaemic in 51 (65%) patients, 3 (4%) patients had mixed ICM/NICM. Of the 27 (35%) patients with infarct, 19 (70%) had invasive coronary angiography and 7 were revascularized (26%). In those without infarct, 39 patients had invasive coronary assessment (76%) and none were revascularized. CMR changed management in 54 (64%) patients including change in medication (53/54, 98%) and device therapy (7/54, 13%).12 (14%) patients were re-admitted within 30 days. There were MACE in 5 (6%) patients including decompensated heart failure, arrhythmia (VT) and stroke, 2 (2%) died during admission and 3 (4%) patients died within 90 days following discharge.DiscussionCMR has a significant impact on the management of patients admitted to a specialist HFU, more so than coronary angiography and informed further management decisions regarding medication changes, re-vascularisation strategies and device implantation.ConclusionCMR has a vital role in the management of inpatients with acute heart failure enabling accurate diagnosis and facilitating a tailored management approach.

Heart disease: Coronary heart disease is a major cause of mortality and morbidity in the UK and globally. It is managed with medical therapy and coronary revascularisation to reduce symptoms and reduce risk of major adverse cardiovascular events. When patients present with chest pain, it is important to risk stratify those that would most benefit from invasive coronary assessment and those that can be managed with medical therapy alone. Myocardial perfusion techniques have been developed in order to do this. Cardiovascular magnetic resonance (CMR) with stress perfusion: CMR allows the non-invasive assessment of coronary artery disease (CAD). Under conditions of vasodilator stress, a gadolinium based contrast agent is injected and during the first pass through the left ventricle, perfusion defects can be observed. There is a strong evidence base for perfusion CMR but the technique is qualitative, relies on experienced operators and potentially misses globally low perfusion such as in cases of \"balanced\" ischaemia. Quantitative perfusion CMR: In contrast, quantitative perfusion techniques allow the calculation of myocardial blood flow (MBF). It is more objective, less reliant on the expert observer and can give additional insights into microvascular disease and cardiomyopathy. As well as being less subjective, quantitative perfusion has other advantages for example it allows full assessment of ischaemic burden and may contain prognostic information that could be used to risk stratify and improve patient care. However, quantitative perfusion has been outside the realm of routine clinical practice due to difficulties in acquiring suitable data for full quantification and the laborious nature of analysing it. Perfusion mapping: Peter Kellman, Hui Xue and colleagues at the National Institutes for Health, USA developed the \"perfusion mapping\" technique to address these limitations. Perfusion maps are generated automatically and inline during the CMR scan and each voxel encodes myocardial blood flow. This allows the instant quantification of MBF without complex acquisition techniques and post processing. In this thesis I have taken perfusion mapping and deployed in the real-world at a scale an order of magnitude higher than prior quantitative perfusion studies, developing the evidence base for routine clinical use across a broad range of diseases and scenarios: In coronary artery disease: I have shown that perfusion mapping is accurate to detect coronary artery stenosis as defined by 3D quantitative coronary angiography in a single centre, 50 patient study. Transmural and subendocardial perfusion are particularly sensitive to detect coronary stenoses with performances similar to expert readers. There is a high sensitivity and high negative predictive value making perfusion mapping a good \"rule-out\" test for coronary disease. Quantitative perfusion and prognosis: I investigated whether stress MBF and myocardial perfusion reserve (MPR) calculated by perfusion mapping would encode prognostic information in a 1049 patient multi-centre study over a mean follow up time of 605 days. Both stress MBF and MPR were independently associated with death and major adverse cardiovascular events (MACE). The hazard ratio for MACE was 2.14 for each 1ml/g/min decrease in stress MBF and 1.74 for each unit decrease in MPR. This work can now be taken forward with prospective studies in order to better risk stratify patients, including those without perfusion defects on clinical read. Reference ranges and non-obstructive coronary disease: I sought to determine the factors that contribute to perfusion in a multi-centre registry study. In patients with no obstructive coronary artery disease, stress MBF was reduced with age, diabetes, left ventricular hypertrophy (LVH) and the use of beta blockers. Rest MBF was influenced by sex (higher in females) and reduced with beta blockers. This study suggests patient factors beyond coronary artery disease (and therefore likely microvascular disease) should also be considered when interpreting quantitative perfusion studies. In cardiomyopathy: I also investigated myocardial perfusion in cardiomyopathy looking at Fabry disease as an example disease. In a prospective, observational, single centre study of 44 patients and 27 controls I found Fabry patients had reduced perfusion (and therefore likely microvascular dysfunction), particularly in the subendocardium and was associated with left ventricular hypertrophy (LVH), glycophospholipid storage and scar. Perfusion was reduced even in patients without LVH suggesting it is an early disease marker. In conclusion, in this thesis, I have developed an evidence base for quantitative perfusion CMR and demonstrated how it can be integrated into routine clinical care. Perfusion mapping is accurate for detecting coronary artery stenosis and encodes prognostic information. Further work in this area could enable patients to be risk stratified based on their myocardial perfusion in order to reduce the morbidity and mortality associated with epicardial and microvascular coronary artery disease. Following on from this work, two further British Heart Foundation Clinical Research Training Fellowships have been awarded to further investigate quantitative perfusion in patients following surgical revascularisation of coronary disease and in patients with hypertrophic cardiomyopathy.