Myocardial Blood Flow Research Articles

Assessment of impact of left ventricular flow state on myocardial blood flow using positron emission tomography and echocardiography

Abstract Background The relationship between left ventricular (LV) mass and myocardial blood flow (MBF) has been recognized as an important physiological measure of myocardial perfusion to match global metabolic demand. However, there is little information on the association between LV flow state and MBF. Purpose To investigate impact of LV flow state on MBF. Methods The study included 104 patients undergoing cardiac positron emission tomography (PET) and echocardiography for chest pain and/or dyspnoea. CT attenuation corrected rest/regadenoson stress 13N-ammonia myocardial perfusion imaging was acquired with a PET CT camera. All images were acquired in 3-D list mode. Sixteen dynamic frames were reconstructed and analyzed with QPET software to obtain rest quantitative MBF measurements adjusted for rate-pressure product in ml/min/g, with a myocardial flow reserve (MFR) derived as the ratio of stress MBF/resting MBF. All patients had no ischaemia or infarction with LV ejection fraction ≥55%. Echocardiography was performed within 6 months of PET in clinically stable conditions allowing for. SV was measured by Doppler echocardiography using the continuity equation and was indexed by body surface area (SVi). The patients were divided to normal flow group (NFS: SVi > 35 ml/m2) and low flow group (LFS: SVi≤35 ml/m2). Results The mean SVi was 40 ml/m2 for NFS and 29 ml/m2 for LFS (p<0.001). LFS group was younger (57 ± 11 vs. 67 ± 11 years, p<0.001) with higher body mass index (43±8 vs. 37±8 kg/m2, p<0.001) and lower resting MBF (0.84±0.22 vs. 1.02±0.34 ml/min/g, p<0.01) than NFS groups. There were no significant differences of hypertension (81% vs. 82%, p> 0.05), LV mass index (82±21 vs. 88±82 g/m2, p>0.05), LVEF (63% vs. 65%, p>0.05) between LFS and NFS groups. SVi was positively associated with MBF as a whole group (r= 0.38, p<0.01). However, this significant association was only observed in NFS group (r=0.62, p <0.001), but not in LFS group (r=0.048, p= 0.46, Figure). Conclusion LFS expressed low MBF and the dissociation between SVi and MBF in comparison with NFS group suggesting potential alterations in relationships between myocardial work (SV) and oxygen consumption (MBF) in LFS. Further studies are warranted to investigate the pathophysiology behind the findings and to correlate with a long-term clinical outcome.

Long-term prognostic impact of fasting plasma glucose and myocardial flow reserve beyond other risk factors and heart disease phenotypes

Abstract Background Cardiometabolic risk factors, including high fasting plasma glucose (hFPG), are emerging determinants of residual mortality risk in patients with coronary artery disease (CAD) or heart failure (HF). Coronary microvascular dysfunction, encompassing a broad spectrum of traditional and emerging risk factors, might be a comprehensive risk predictor in these patients. Purpose To assess whether hFPG and global myocardial blood flow (MBF) reserve measured by positron emission tomography (PET), expressing global coronary function, may predict long-term prognosis beyond other risk factors and the presence of obstructive CAD or left ventricular (LV) dysfunction associated with HF. Methods Among 281 consecutive patients undergoing cardiac PET/CT because of stable chest pain or dyspnea we retrospectively collected long-term follow-up data in 103 patients (mean age 61±10 years, 74 males) in whom MBF measurements, coronary angiography and clinical data were available. Disease phenotypes included obstructive CAD (35%), LV dysfunction without obstructive CAD (43%) or none (22%). Results The mean age was 61±10 years (74 males, 72%). Among CVD risk factors, high LDL-cholesterol (hypercholesterolemia under treatment or LDL-C> 130 mg/dL) was present in 72%, high systemic blood pressure (hypertension under treatment or SBP>130/85 mmHg) in 51%, smoking habits in 49%, obesity (BMI>30 Kg/m2) in 22%, type 2 diabetes under treatment in 17%, low HDL-cholesterol (HDL-C< 40 mg/dL in males and <50 mg/dL in females) in 51%, high triglycerides (TG>150 mg/dL) in 27% and high fasting plasma glucose (FPG>100 mg/dL) in 33%. Global MBF reserve was <2 in 68% of patients. In a median follow-up of 10.9 years (7.8-13.9 IQR), 39 patients (37.8%) died (13.6% cardiac death). At multivariable Cox analyses including all risk factors and MBF reserve, age (HR 1.06, 95% CI 1.02-1.11), high FPG (HR 2.28, 95% CI 1.09-4.79) and depressed MBF reserve (HR 4.79, 95% CI 2.14-10.69) were the only independent predictors of death (Global χ2 36.74, P=0.0001). When disease phenotypes were added to the model, age (HR 1.07, 95% CI 1.02-1.12), high FPG (HR 2.18, 95% CI 1.02-4.63) and depressed MBF reserve (HR 4.47, 95% CI 1.96-10.18) remained independent predictors of death (Global χ2 37.41, P=0.0004) (Figure 1). Figure 2 plots the observed all cause death rate in patients with different disease phenotypes stratified for absence/presence of high FPG or MBF reserve <2. Death rate progressively increases according to disease phenotypes and is significantly associated with high FPG (P=0.049) or impaired MBF reserve (P=0.012) in each patient group. Conclusions These results suggest a strong long-term prognostic role of high FPG and depressed MBF reserve in a selected high-risk population of patients with high prevalence of obstructive CAD or HF.Figure 1 Figure 2

Cardiac structural, functional remodelling, and perfusion impairments across the spectrum of aortic stenosis

Abstract Background Aortic stenosis (AS) accounts for substantial global morbidity and premature mortality even in moderate AS (Mod-AS). Whilst myocardial remodeling response is considered critical in the adverse prognosis of Mod-AS, the precise mechanisms remain poorly understood. We aimed to prospectively assess myocardial remodeling, perfusion and energetics differences in Mod-AS and severe AS (Severe-AS). Methods Fifty-two Severe-AS and 25 Mod-AS patients and 18 demographically-matched controls underwent cardiovascular magnetic resonance and phosphorus-magnetic resonance spectroscopy to define left ventricular (LV) mass and function, global longitudinal shortening (GLS), rest and adenosine-stress myocardial blood flow (MBF), myocardial perfusion reserve (MPR), layer-specific perfusion metrics (subendocardial [Endo], subepicardial [Epi] MBF and MPR, and Endo-Epi-MBF ratio [Endo/Epi]), myocardial scar on late gadolinium enhancement (LGE) imaging, and myocardial energetics (phosphocreatine:ATP ratio [PCr/ATP]). Results Compared to controls, with increasing AS severity, there was progressive increase in LV concentricity (LV mass-index (controls: 46[40,51],Mod-AS:58[51,65],Severe-AS: 70[65,75]g/m2; P<0.0001), and stepwise decline in GLS (controls:19.9[17.6,22.2], Mod-AS:17.7[16.6,18.8], Severe-AS:13.4[12.5,14.4]%; P<0.0001) with significant differences between Mod-AS and Severe-AS in all three comparisons. Both stress MBF(controls:2.1[1.9,2.3],Mod-AS:1.9[1.6,2.2],Severe-AS:1.3[1.2,1.5]ml/min/g; P<0.0001) and MPR(controls:3.3[2.8,3.6],Mod-AS:2.8[2.4,3.2], Severe-AS:1.9[1.8,2.1]; P<0.0001) were only significantly reduced in Severe-AS compared to controls, with significant differences also detected between Mod-AS and Severe-AS. However, stress-endo-MBF (controls:2.0[1.8,2.3], Mod-AS:1.7[1.5,2.0], Severe-AS:1.2[1.1,1.3]ml/min/g; P<0.0001), stress-Endo/Epi(controls:1.00[0.93,1.07],Mod-AS:0.87[0.80,0.94],Severe-AS:0.81[0.75,0.82];P<0.0001), rest-Endo/Epi (controls:1.12[1.10,1.14], Mod-AS:1.06[1.03,1.09], Severe-AS:1.03[1.02,1.06]; P<0.0001) and endo-MPR (controls:3.2[2.7,3.6],Mod-AS:2.5[2.1,2.9],Severe-AS:1.7[1.5,1.8]; P<0.0001) were all significantly reduced in both Mod-AS and Severe-AS. Compared to controls, both AS groups showed significantly lower PCr/ATP (controls:2.2[2.0,2.3],Mod-AS:1.8[1.6,2.0],Severe-AS:1.7[1.6,1.8]; P<0.0001). Only the Severe-AS group had evidence of non-ischemic myocardial scarring on LGE (2.9[0.0,6.2]%), which was detected in 65%(n=34) of patients. AS severity (peak aortic valve velocity) correlated with stress-MBF (r=-0.45, P=0.0003), MPR (r=-0.44, P=0.0005) and GLS (r=-0.47, P=0.0001). Conclusions Moderate and severe-AS are both associated with cardiac concentric hypertrophy, reductions in myocardial energetics, and subendocardial hypoperfusion. Patients with Severe-AS exhibit a more pronounced phenotype with worse LV hypertrophy, contractile dysfunction and myocardial scarring compared to Mod-AS patients.

Quantitative perfusion by cardiac magnetic resonance analysis reveals compromised myocardial perfusion in patients with angina with non-obstructive coronary artery disease

Abstract Introduction Stress perfusion cardiac magnetic resonance (CMR) visually detects myocardial ischemia through first-pass contrast-enhanced imaging by identifying perfusion defects. However, in generalized myocardial diseases like angina with non-obstructed coronary arteries (ANOCA), visual assessment becomes challenging due to diffuse sub-endocardial perfusion defects, or the findings may even falsely appear normal. Fully automated quantitative perfusion (QP), allowing absolute quantification of myocardial blood flow (MBF) and deriving myocardial perfusion reserve (MPR), might increase diagnostic accuracy in ANOCA patients. Therefore, the purpose of this study is to test the use of QP in detecting ANOCA diagnosed by the invasive golden standard. Methods This study is a cross-sectional cohort study assessing the use of fully automated QP CMR in patients with ANOCA compared with age- and sex-matched healthy controls. All participants underwent adenosine stress perfusion CMR, including visual assessment and quantification of MBF and MPR. Furthermore, all ANOCA patients underwent intracoronary function testing (ICFT) to idenity vasospasm and/or coronary microvascular dysfunction. Results This study included 24 ANOCA patients (83% women, 56.8±8.9 years) and 25 healthy controls (80% women, 56.2±7.2 years). Visual perfusion assessment showed no group differences in terms of perfusion defects (p=0.536). However, in QP, ANOCA patients had higher relative MBF than healthy controls (0.83±0.15 vs 0.74±0.17, p=0.046), while global perfusion was significantly lower during stress (2.43±0.72 vs 2.99±0.65 ml/g/min, p=0.006). Moreover, ANOCA patients had significantly lower MPR than healthy controls (2.24 ±0.79 vs 2.68 ±0.64, respectively p=0.036), with a higher prevalence of an impared MPR (50% vs. 20%, p=0.027). MPR was not significantly different between the various ANOCA entities as stratified during ICFT (p=0.766). Conclusions ANOCA patients displayed significantly reduced MPR, indicating impaired perfusion. The prevalence of diminished MPR was higher in the ANOCA group compared to the healthy controls, constrasting with no differences in visual assessment. These results are promising and underscores the possibilities of the use of QP in detecting vasomotor dysfunction non-invasively in ANOCA patients.Quantitative Perfusion by CMR results

Quantitative myocardial blood flow distribution derived from CCTA and determination of myocardium at risk in the FAST TRACK CABG trial

Abstract Background In the anatomic SYNTAX score derived from invasive coronary angiography, the ischemic impact of each stenotic coronary segment is weighed with a fixed score based on the severity of luminal diameter narrowing and the theoretical amount of blood flow supplied to the myocardium(1). This method neither accounts for individual variation nor reflects the true extent of myocardium ischemia. Purpose We aim to provide a quantitative CT SYNTAX score derived from coronary computed tomography angiography (CCTA) with customized percent blood flow distribution to the myocardium supplied by each stenotic coronary segment to determine the myocardium at risk of ischemia. Methods Patients with 3VD and/or left main coronary artery disease (CAD) were included in the first-in-human FAST TRACK CABG trial and received surgical revascularization guided solely by CCTA and fractional flow reserve derived from CCTA (FFRCT). The recently reported anatomic CT-SYNTAX score was calculated for all cases. The FFRCT value and percent myocardial blood flow distribution(%MBF) were computed for all 16 SYNTAX score segments using the validated method of Keulards et al(2). On the pre-CABG CCTA, the segments located distal to the site where the FFRCT value dropped below 0.80 were considered at risk of ischemia, and the individual weight point per segment was calculated as 6×%MBF for each segment. The SYNTAX score derived from %MBF is compared to the anatomic and functional CT-SYNTAX score. Results Out of 114 patients enrolled, FFRCT and %MBF were analyzable in 106 patients. After excluding vessels with total occlusion, the coronary flow distribution between the right and left coronary systems was 20.5% vs 79.5%, respectively, similar to the 1:5 ratio in the anatomic SYNTAX score. The anatomic and functional CT-SYNTAX scores were 43.6 and 41.1, respectively. The average total %MBF per patient was 72.0(19.1)%, and the average SYNTAX score derived from %MBF was 38.0. There is a strong correlation between functional SYNTAX score and SYNTAX score derived from %MBF (Peason’s R=0.93). Passing-Bablock regression trends showed that the functional SYNTAX score slightly overestimated the SYNTAX score derived from %MBF (Figure 1). The coronary segment weight varied significantly per individual, especially in the presence of total occlusion. Overall, the fixed weight of the anatomic SYNTAX score is a good surrogate for the individualized weighing based on %MBF (Figure 2). Conclusion CCTA-derived %MBF enabled clinicians to quantify the individualized myocardium at risk of ischemia or injury in patients with severe CAD. Retrospectively, the fixed weight score used in the anatomical SYNTAX score appeared to be a robust surrogate for myocardial blood flow distribution.Figure 1Figure 2

Coronary microvascular dysfunction as assessed by cardiac MRI and its association with aerobic exercise capacity in dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) has a poor prognosis. Aerobic exercise capacity (peak VO2) is an independent predictor of mortality but the central mechanisms contributing to exercise intolerance in DCM are unknown. Purpose To characterise myocardial perfusion reserve (MPR) and determine if cardiovascular magnetic resonance (CMR) measures of structure, function and microvascular function are associated with aerobic exercise capacity in DCM. Methods Single centre, prospective, case-control comparison of adults with DCM and matched controls. Adenosine-stress perfusion CMR to assess cardiac structure, function and quantitative perfusion, and cardiopulmonary exercise testing (CPET) to determine peak VO2, was performed. Controls were propensity matched based on age, sex, body mass index and diabetes status, and between group comparison was adjusted for other key clinical characteristics (CMR: ethnicity and systolic blood pressure; CPET: ethnicity, systolic blood pressure, smoking history and lung disease). Comparison of perfusion in segments with and without late gadolinium enhancement was performed using mixed effects linear regression taking into account individual patient segmental perfusion. Pre-specified multivariable linear regression, including key clinical and cardiac variables, was undertaken in patients with DCM to identify independent associations with percentage predicted peak VO2, which incorporates age, sex, height and weight. Results Sixty-six patients with DCM (median age 61 years, 71% male) were matched to 66 controls (median age 59 years, 71% male). The DCM group had greater left ventricular (LV) end-diastolic and end-systolic volumes, lower systolic and diastolic function, and had more focal and diffuse fibrosis compared to controls (Table 1). There was lower rest (0.58±0.14 versus 0.65±0.17 mL/min/g; P=0.033) and stress (1.53±0.49 versus 2.01±0.60 mL/g/min; P<0.001) myocardial blood flow, and lower MPR (2.69±0.84 versus 3.15±0.84 mL/g/min; P=0.002) in the DCM group. In DCM patients, mixed effects linear regression demonstrated lower rest (adjusted mean 0.54(95% CI 0.50-0.57) versus 0.58(0.55-0.62) mL/g/min; P<0.001) and stress MBF (1.38(1.25-1.51) versus 1.55(1.43-1.67) mL/g/min; P<0.001) in segments with LGE compared to segments without LGE, but there was no difference in MPR (2.71(2.47-2.96) versus 2.76(2.55-2.97) mL/g/min; P=0.496). DCM patients had markedly lower peak VO2 (19.8±5.5 versus 25.2±7.3 mL/kg/min; P<0.001). Multivariable linear regression demonstrated that LV ejection fraction, extracellular volume fraction and MPR, but not LV mass, were independently associated with percentage predicted peak VO2 in DCM (R squared=0.531, P<0.001; Table 2). Conclusions DCM patients have lower rest and stress myocardial blood flow and lower MPR compared to controls. In DCM, MPR, LV ejection fraction and fibrosis are independently associated with aerobic exercise capacity.

Prognostic value of the right coronary venous anatomy in patients undergoing cardiac resynchronization therapy

Abstract Background The size and distribution of the coronary veins (CV) reflect both intracavitary pressure and myocardial blood flow, and therefore, in patients with cardiomyopathy, CV anatomy could potentially become a biomarker of disease severity. While the left coronary veins have been well described, there are few descriptions of the right CV system. Purpose Given these considerations, the aim of the study was to evaluate the anatomy of the right CV system and its potential prognostic significance in patients with advanced cardiomyopathy. Methods We analyzed CV angiograms from 121 patients (age 67±14 years) undergoing cardiac resynchronization therapy (CRT). The right ventricular (RV) veins were seen to fill during the injection of contrast through multiple connections with the left sided venous system. Patients were followed for a median of 43 [IQR 3-73] months, during which 12 patients expired. Results Anterior cardiac veins (ACV), which overlay the RV wall were observed in 85 (70%) patients and had a maximum ostial diameter of 2.04±0.8 mm. Multiple ACVs were seen in 62 patients. These veins were observed to empty directly into the venous sinus of right atrium (VSRA), into the RV, the right atrium (RA), or into the small cardiac vein (SCV) in 68, 9, 5, and 3 patients respectively. The right marginal vein (RMV) was visualized in 21 (17%) patients, had a diameter of 2.3±1.2 mm, and ran a course along the right border of the RV, emptying directly into RV, RA or into VSRA in 9, 4 and 8 patients respectively. The VSRA present in 91 (75%) patients, coursed parallel to the right coronary sulcus, collecting blood from the ACV’s and RMV’s and drained into the RA (Figure A); in 7 patients, 2 VSRA ostia were noted. VSRA lengths and diameters varied (11-119 mm, mean 41±25 mm) and (1.2-6.9mm, mean 2.7±1.2mm) respectively. The VSRA lengths correlated significantly with RV fractional area change, RV systolic pressure, tricuspid regurgitation severity evaluated by echocardiography, and P wave amplitude in ECG lead II (r=-0.65; p=0.041, r=0.88; p=0.019, r=0.52; p=0.030, and r=0.79; p=0.031 respectively). The VSRA diameters, which were significantly larger in patients with obstructive sleep apnea (3.6±1.5 vs. 2.3±1.2mm; p=0.021) correlated significantly with RV systolic pressure, and tricuspid regurgitation severity by echocardiography (r=0.77; p=0.009, and r=0.63; p=0.006 respectively). Patients who expired during follow-up had a significantly longer VSRA than patients who remained alive (Figure B). The VSRA length, RV fractional area change, and baseline QRS duration independently predicted survival in a Cox multivariate model that also included age and left ventricular ejection fraction. Conclusions RV venous system demonstrates a highly variable anatomy that has not been previously well described. The size of the VSRA correlated with parameters of RV function and predicted survival in patients undergoing CRT.Figure

Serial quantitative stress perfusion cardiac magnetic resonance in patients undergoing coronary artery bypass grafting; prediction of symptomatic benefit

Abstract Background Serial multiparametric cardiovascular magnetic resonance (CMR) in patients undergoing coronary artery bypass grafting (CABG) may provide mechanistic insight into dynamic and persistent abnormalities of the myocardium in patients with stable coronary artery disease (CAD). Objectives To assess for dynamic CMR markers of myocardial hypoperfusion and cardiac remodelling in patients undergoing CABG. Methods Patients with CAD awaiting elective CABG were recruited into an observational cohort study. Baseline evaluation included bloods, Seattle Angina Questionnaire-7, and adenosine stress perfusion CMR. Automated fully quantitative stress and rest myocardial blood flow was calculated, alongside assessment of the visual ischaemic burden. Native and post-contrast septal T1 indices were also measured. Repeat evaluation at 6-12 months post CABG was performed. Results Of 43 patients who underwent serial evaluation with CMR (mean age 62.1±9.3, median LVEF 68% [IQR: 62-73%]), there was improvement in the median visual ischaemic burden (18% [IQR: 11-21] vs 42% [IQR: 27-51], P<0.001), mean global stress myocardial blood flow (1.5±0.5 ml/min/g vs 1.3±0.5 ml/min/g, P=0.002) and median global myocardial perfusion reserve (2.4 [IQR: 1.7-2.8] vs 1.7 [IQR: 1.4-2.2], P=0.002) following CABG. Greater improvement in the SAQ-7 summary score was associated with a larger visual ischaemic burden at baseline (ρ=0.44, P=0.004) and a greater decrease in the visual ischaemic burden following CABG (ρ=-0.38, P=0.02). Quantitative MBF metrics did not associate with baseline or change in SAQ-7 summary score. Mean LV extracellular matrix volume decreased following CABG (16.6±3.6ml/m2 vs 18.2±4.6ml/m2, P=0.009). Conclusion Multiparametric CMR identifies dynamic changes in markers of myocardial perfusion and interstitial fibrosis in patients following CABG. Visual assessment of inducible myocardial hypoperfusion may identify patients who will derive the most symptomatic benefit from CABG. The results, however, suggest an important degree of residual inducible ischaemia and an unclear clinical role for CMR-derived MBF calculations.Serial CMR perfusion dataAssociation of SAQ with perfusion

The impact of type 2 diabetes on short term myocardial morphological, functional, and energetic recovery post coronary artery bypass surgery in patients with ischemic heart disease

Abstract Background Type 2 diabetes (T2D) confers three times higher mortality in patients with ischemic heart disease (IHD). Moreover, amongst patients with IHD those with diabetes were shown to have higher long-term mortality from heart failure despite angiographic or surgical revascularisation with coronary artery bypass grafting (CABG). Impaired myocardial structural, functional, and energetic recovery may underpin this epidemiological observation. Consequently, using cardiovascular magnetic resonance and phosphorus-magnetic resonance spectroscopy scans, we aimed to assess the effect of T2D comorbidity on myocardial structural, functional, perfusion, and energetic recovery post-CABG in patients with IHD. Methods Seventy-seven IHD patients with (n=39) and without T2D (n=38) awaiting CABG were recruited. One-month pre- and 6-months post-CABG, cardiac phosphocreatine to ATP ratio (PCr/ATP), global longitudinal shortening (GLS) and 6-minute walk-distance (6MWD) were assessed in the study cohorts. The rest and adenosine-stress myocardial blood flow (MBF) assessments were only performed 6-months post-CABG. Results Pre-CABG, IHD-T2D patients had higher LV concentricity (LV mass to LV end diastolic volume ratio) (IHD-T2D:0.84[0.74,0.93],IHD-noT2D:0.72[0.67,0.77]g/mL,P=0.03]. worse PCr/ATP T2D (IHD-T2D:1.5[1.4,1.7],IHD-noT2D:1.8[1.6, 2.0];P=0.03) and shorter 6-minute walk distance (IHD-T2D:338[307,370],IHD-noT2D:399[364,434]m,P=0.007). There were no significant differences in LV volumes, ejection fraction or GLS between the two groups pre-CABG. Post-CABG, there was no longer a significant difference in cardiac energetics or 6-minute walk distances between the two groups due to a significant improvement in PCr/ATP in the IHD-T2D group. LV concentricity remained significantly elevated in the IHD-T2D group post CABG (IHD-T2D:0.82[0.75,0.88],IHD-noT2D:0.73[0.68,0.79]g/mL,P=0.04). Neither group showed a significant change in LVEF or GLS from the pre-CABG values, and post-CABG there were no differences in the rest or stress myocardial blood flows between the two groups. Conclusions Six months after CABG, neither IHD patients with T2D, nor IHD patients without T2D show any significant changes in LV structural remodelling or in contractile function. T2D does not jeopardise the short-term recovery in myocardial energetics or exercise distance post-CABG, with IHD patients with T2D showing more pronounced improvements post-CABG in both these assessments than patients without T2D. Larger longitudinal studies are needed to better understand the mechanisms of adverse longer-term cardiovascular outcomes suggested by epidemiological studies in IHD patients with T2D.

Zibotentan in microvascular angina: a randomized, placebo-controlled, crossover trial

Abstract Background/Introduction Microvascular angina is a chronic condition characterized by abnormal myocardial blood flow leading to ischemic symptoms. Endothelin-1, a peptide secreted by endothelial cells, is a highly potent constrictor of the human coronary arterioles. Microvascular angina is associated with elevated circulating concentrations of endothelin-1, and prolonged exposure to ‘excess’ endothelin causes vasoconstriction and vascular remodelling. The chronic elevation of circulating endothelin-1 in microvascular angina may be influenced by genetic factors. Purpose Zibotentan, the most selective antagonist of the endothelin A receptor with no off-target binding to the endothelin B receptor, was evaluated in oncology trials and did not improve survival. We identified zibotentan as a potential disease-modifying therapy for patients suffering from microvascular angina. We hypothesized that zibotentan 10 mg daily for 12 weeks in addition to background medical therapy could be an efficacious and safe treatment for patients with microvascular angina. We further hypothesized that the SNP regulator of EDN1 gene expression, rs9349379 (G allele), could be a novel theragnostic biomarker. Methods The trial involved a prospective, multicentre, randomized, double-blind, placebo-controlled, sequential crossover design to assess the effects of zibotentan 10 mg or matched placebo, once daily for 12 weeks. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The secondary outcomes included exercise test parameters, health status questionnaires, safety (frequency and severity of severe adverse events (SAEs) and adverse events), feasibility (withdrawal rate), and biomarkers of efficacy (pharmacokinetics, pharmacodynamics). Results The study found no significant difference in exercise duration with zibotentan (-4.26 seconds; 95% CI: -19.60 to 11.06; P=0.5871). There was no effect on the secondary outcomes. However, for exploratory (mechanistic) outcomes, zibotentan increased plasma big endothelin-1, endothelin-1, and global myocardial blood flow, while reducing hemoglobin, diastolic, and systolic blood pressure (all p<0.001). Adverse events were more common during the zibotentan period (60.2%) compared to placebo (14.4%, p<0.001). Conclusion(s) In conclusion, daily administration of 10 mg zibotentan for 12 weeks did not enhance exercise duration and was commonly associated with adverse effects related to fluid retention. Further trials exploring lower zibotentan doses in combination with agents to mitigate fluid retention, and longer treatment durations, are warranted.

A randomized, double-blind, placebo-controlled, mechanistic trial on the safety, tolerability and pharmacodynamics of ninerafaxstat in patients with angina and chronic coronary syndrome

Abstract Background/Introduction Symptoms of angina resulting from reversible myocardial ischemia in chronic coronary syndromes have a negative impact on quality of life. Metabolic alterations are a key feature of ischemia, including reduced ATP generation by mitochondrial oxidative phosphorylation, NAD+ depletion, anaerobic glycolysis, proton & lactate accumulation leading to contractile dysfunction. Ninerafaxstat is a novel cardiac mitotrope that shifts metabolism from fatty acids towards glucose utilization, optimizing myocardial energy production during ischemia. Purpose We aimed to investigate the safety, tolerability, impact on myocardial glucose utilization and preliminary anti-ischemic efficacy of ninerafaxstat administered for 8 weeks to patients with symptomatic chronic stable angina who were on anti-anginal therapy and had evidence of myocardial stress hypoperfusion using 15O-H2O PET imaging. Methods IMPROVE-Ischemia was an international, randomized, double-blind, placebo-controlled mechanistic trial comparing ninerafaxstat vs. placebo in patients with symptomatic chronic coronary syndrome. The primary endpoint was the safety and tolerability of ninerafaxstat. Key efficacy evaluations were undertaken at baseline and end-of-treatment (Week 8) including imaging core laboratory assessments of 15O-H2O PET perfusion rest and stress imaging to quantify absolute myocardial blood flow (MBF), dobutamine stress echo with contrast for evaluation of LV contractile response during demand stress using the wall motion score index (WMSI) and, in a subgroup of subjects, 18F-FDG-PET imaging of myocardial glucose metabolism. Results The study randomized 58 subjects (mean age 68.6±7.1 years) with symptomatic stable angina and inducible hypoperfusion from 4 sites across 3 countries (Denmark, Finland, Sweden). 22% had type 2 diabetes and 50% had undergone percutaneous and/or surgical coronary revascularization. The majority (68%) were on ≥2 (up to 4) regular anti-anginals. Ninerafaxstat was well tolerated without impact on systemic hemodynamics. At Week 8, ninerafaxstat significantly increased myocardial glucose utilization and, in those with dobutamine-induced deterioration in wall motion at baseline assessment (n=25, pre-specified subgroup), resulted in a ~50% improvement in mean and peak stress WMSI, without altering rest or hyperemic stress MBF (Table 1). Conclusion(s) Treatment with ninerafaxstat was well-tolerated and showed a neutral hemodynamic profile. Ninerafaxstat significantly increased myocardial glucose utilization consistent with its mechanism of action and improved myocardial contractile response to dobutamine stress in subjects with baseline stress inducible deterioration of wall motion. These findings support a direct, metabolically-mediated, anti-ischemic effect of ninerafaxstat on top of existing anti-anginal agents, supporting its further development in cardiac pathologies characterised by ischemia.

Prognostic value of quantitative anatomical and functional measures of coronary artery disease in diabetic and non-diabetic patients

Abstract Background Diabetes is associated with increased risk of coronary artery disease (CAD). However, the relative prognostic importance of anatomical and functional findings of CAD in the presence vs. absence of diabetes is incompletely understood. Technological advances have made quantitative analysis of coronary artery plaques and stenosis feasible by coronary computed tomography angiography (CTA). In turn, positron emission tomography (PET) enables absolute quantification of myocardial blood flow (MBF). Purpose To study long-term prognostic value of quantified severity of coronary atherosclerosis and myocardial perfusion in non-diabetic vs. diabetic patients with suspected CAD. Methods From two academic medical centres, we identified symptomatic patients with suspected CAD who had undergone coronary CTA and [15O]H2O PET myocardial perfusion imaging during adenosine stress. Based on artificial intelligence -guided quantitative analysis of coronary CTA scans, the anatomical severity of CAD was measured as the presence of obstructive CAD (≥50% diameter stenosis) and percent atheroma volume (PAV; higher vs. lower than median). The functional severity of CAD was measured as the presence of regional myocardial ischemia (≥2 adjacent segments with stress MBF <2.3 ml/g/min) and global stress MBF (<2.2 ml/g/min vs. ≥ 2.2 ml/g/min) by PET. Annual rates of adverse events (AER) including all-cause mortality, myocardial infarction (MI), and unstable angina pectoris (UAP) were evaluated. Results Among 1311 patients, 251 (19%) had diabetes. Patients with diabetes had more frequently obstructive CAD (55% vs. 43%, p<0.001) and regional myocardial ischemia (51% vs. 43%, p=0.015), higher plaque burden by PAV (12% vs. 7%, p<0.001), and lower global stress MBF (2.78 ml/g/min vs. 3.05 ml/g/min, p<0.001). During median follow-up of 7.1 years, 171 (13.0%) patients experienced AE (85 deaths, 56 MIs, and 30 UAPs). Patients with diabetes had higher AER than non-diabetic patients (3.1% vs. 1.6%, p<0.001). The presence of obstructive stenosis was associated with increased AER in non-diabetic (2.6% vs. 1.0%, p<0.001) and diabetic patients (4.2% vs. 1.9%, p<0.001). High plaque burden by PAV was associated with increased AER in non-diabetic (2.8% vs. 0.7%, p<0.001) and diabetic patients (3.9% vs. 1.7%, p<0.001). The presence of regional myocardial ischemia was associated with increased AER in non-diabetic (2.5% vs. 1.1%, p<0.001), but not in diabetic patients (3.4% vs. 2.7%, p=0.238). Low global stress MBF was associated with increased AER in non-diabetic (2.9% vs. 1.3%, p<0.001), but not among diabetic patients (3.2% vs. 3.0%, p=0.286). Conclusions Diabetes was associated with more advanced CAD. Quantified severity of anatomical findings predicted long-term adverse outcome in non-diabetic and diabetic patients. In contrast, functional imaging risk stratified non-diabetic patients, whereas diabetic patients had impaired long-term outcome irrespective of perfusion findings.

Effect of exogenous ketone supplementation on cardiac energetics, function, and perfusion in type 2 diabetes, heart failure, and healthy participants- A single center, open labelled clinical study

Abstract Background Type 2 diabetes (T2D) confers loss of cardiac metabolic flexibility in fuel selection and impaired mitochondrial function. Enhanced ketone metabolism observed in T2D may represent a compensatory adaptive mechanism as ketones are a more energy efficient resource than carbohydrates or fatty acids. Favorable energetic properties of ketones may potentially mitigate the energy starved state in T2D and heart failure (HF). Purpose To test whether exogenous oral ketone supplementation would reverse cardiac energetic deficit, as well as improve cardiac function and perfusion in patients with T2D, with HF with reduced ejection fraction (HFrEF), and healthy volunteers (HV). Methods Three groups of patients were recruited: patients with T2D (n=33); patients with HFrEF (n=29, 14 with T2D); and HVs(n=25). Participants underwent cardiovascular magnetic resonance and spectroscopy to assess left ventricular (LV) function, rest and dobutamine stress perfusion and energetics (phosphocreatine/adenosine triphosphate ratio[PCr/ATP]). After the initial visit, participants had an identical second visit following 2 weeks of oral ketone supplementation (30g daily). Results Participants were matched in age and sex distribution. There were no significant differences in LV ejection fraction (LVEF) between T2D and HV groups with significantly lower LVEF in HFrEF group. Both the T2D group and the HFrEF group showed significant reductions in PCr/ATP ratio and the rest and stress GLS compared to the HV. The resting and dobutamine-stress myocardial blood flow (MBF) were only significantly reduced in patients with HFrEF compared to T2D and HV groups. Subgroup analyses of HFrEF group with and without T2D showed no significant differences in energetics, perfusion, or functional assessments. Significant increase in PCr/ATP ratio was seen only in T2D group from baseline after 2 weeks of ketone supplementation (Visit-1:1.6[1.5,1.8] vs Visit-2:1.9[1.7,2.1]; P=0.01). This significant increment was not observed in HFrEF or HV groups. Two weeks of ketone supplementation was not associated with any significant changes in LVEF, GLS, rest or dobutamine-stress myocardial blood flow, or in myocardial lipid content (Table-1). Conclusions Short-term ketone supplementation is associated with isolated significant improvements in resting cardiac energetics in patients with T2D and preserved LVEF, without changes cardiac function or perfusion. In contrast to patients with T2D and preserved LVEF, short-term ketone supplementation does not lead to any significant improvements in energetics in patients with HFrEF suggesting loss of mitochondrial plasticity with transition to HFrEF. Moreover, healthy volunteers experience no further increments of myocardial energetics from the normal range values at baseline with ketone supplementation.

Predictive factors and gender insights into abnormal myocardial flow reserve in non-obstructive coronary artery disease: a CZT-SPECT analysis

Abstract Background Dynamic myocardial perfusion imaging (D-MPI) using cadmium-zinc-telluride (CZT) cardiac-dedicated SPECT has emerged as a valuable method for assessing coronary microcirculation, particularly compared to conventional SPECT. Additionally, gender-specific disparities in microvascular dysfunction require further investigation. Objective This study aims to identify predictive factors for abnormal myocardial flow reserve (MFR) in non-obstructive coronary artery disease (CAD) using CZT-SPECT, with a focus on gender differences in MFR dysfunction. Methods A retrospective analysis was conducted on clinical data from 393 patients presenting with symptoms of "chest pain and/or tightness," all of whom were confirmed to lack obstructive CAD by coronary angiography or CT angiography. MFR was measured using CZT-SPECT, with values ≥2.5 considered normal and values <2.5 considered abnormal. Results Of the patients, 49.1% (193/393) demonstrated abnormal MFR, with females representing 56.7% (223/393). Females with abnormal MFR exhibited higher averages in age, total cholesterol, LDL-C, creatinine, left atrial diameter, left ventricular posterior wall (LVPW) thickness in diastole, and E/e’ ratio (P < 0.05). Additionally, MDRD-eGFR and mitral annular septal velocity e’ were lower in the abnormal MFR cohort (P < 0.05). Multivariate logistic regression analysis identified elevated LDL-C levels (OR = 1.513, 95%CI: 1.122–2.041, P = 0.007) and increased LVPW thickness (OR = 1.717, 95%CI: 1.140–2.585, P = 0.010) as independent predictors of abnormal MFR in females. ROC analysis suggested optimal cutoff for LDL-C at 3.68 mmol/L (sensitivity 31%, specificity 84%, AUC = 0.586; 95%CI: 0.511–0.661) and LVPW thickness at 9.5 mm (sensitivity 62%, specificity 52%, AUC = 0.576; 95%CI: 0.501–0.652). A combined ROC analysis of LDL-C and LVPW thickness showed a sensitivity of 50% and specificity of 73% (AUC = 0.632, 95%CI: 0.559–0.705). In males, greater left ventricular end-diastolic diameter (LVEDD) was significantly associated with abnormal MFR (P = 0.014), with LVEDD identified as a predictor (OR = 1.130, 95%CI: 1.016–1.258, P = 0.025) and an optimal cutoff at 44.5 mm (sensitivity 88%, specificity 37%, AUC = 0.609; 95%CI: 0.524–0.694). No significant gender differences were observed in overall left ventricular resting myocardial blood flow (MBF) among patients with abnormal MFR (P = 0.072); however, female patients exhibited higher resting MBF in specific territories supplied by the left circumflex and right coronary arteries, and higher E/e’ ratios (P < 0.05). Furthermore, a negative correlation was found between resting MBF in the territory supplied by the right coronary artery and E/e’ in females (r = -0.210, P = 0.030). Conclusion Predictors of abnormal MFR in non-obstructive CAD show gender disparities, implicating an association with left ventricular diastolic function.

Myocardial remodelling in bicuspid aortic valve associated severe aortic stenosis and reverse remodelling after aortic valve replacement

Abstract Background Bicuspid aortic valve (BAV) is a common congenital heart disease and a major risk factor for aortic stenosis (AS). Myocardial remodelling response to AS plays an important prognostic role1. Cardiovascular magnetic resonance (CMR) can evaluate myocardial structure, function and perfusion in AS. Phosphorus magnetic resonance spectroscopy (31P-MRS) can also assess myocardial energetic consequences of AS2. Purpose Assess differences in myocardial remodelling between tricuspid aortic valve (TAV) and BAV-associated severe-AS, and their recovery 6 months post aortic valve replacement (AVR). Methods Eighty severe-AS patients (70[69-72]years) undergoing AVR (40 TAV, 40 BAV) and 21 demographically-matched controls were recruited. AS groups were matched for demographics, AS severity, surgical risk scores and comorbidities. One month before and 6 months post-AVR, patients underwent CMR and 31P-MRS for measuring left ventricular (LV) mass, concentricity-index (LV mass to LV end-diastolic volume ratio), global longitudinal shortening (GLS), rest and adenosine-stress myocardial blood flow (MBF), myocardial perfusion reserve (MPR) and energetics-index phosphocreatine to ATP ratio (PCr/ATP). Results Pre-AVR, there was no significant differences between the three cohorts when assessing LV ejection fraction, indexed LV end-diastolic volume and indexed end-systolic volume. Pre-AVR, both AS groups showed higher LV-concentricity (controls:0.53[0.51,0.60], TAV:0.95[0.82,1.07], BAV:0.92[0.82,1.08]g/ml;P<0.0001), higher mass-index (controls:45[39,50], TAV:73[67,78], BAV:74[68,80]g/m2;P<0.0001), impaired GLS (controls:18.8[16.5,19.5], TAV:12.6[11.3,13.9], BAV:13.6[10.9,16.6]%;P<0.0001). Reductions in both AS groups were also seen in PCr/ATP (controls:2.19[1.85,2.63], TAV:1.64[1.39,1.85], BAV:1.85[1.60,2.10];P=0.0004), stress-MBF (controls:2.16[1.88,2.27], TAV:1.35 [1.16,1.56], BAV:1.36[1.00,1.66]ml/min/g;P<0.0001), and MPR (controls:3.38[2.65,3.92], TAV:2.04 [1.78,2.46], BAV:1.83[1.58,2.78]ml/min/g;P<0.0001) against controls, with no significant differences between TAV and BAV. No significant difference was seen in the proportion of patients with TAV and BAV undergoing transcatheter or surgical AVR (table1). Post-AVR, the TAV and BAV groups experienced similar patterns of reverse LV-remodelling, with no significant differences in LV-concentricity (TAV:0.86[0.71,0.98], BAV:0.81[0.65,0.96];P=0.41), LV-mass-index (TAV:60[54,65], BAV:61[55,66];P=0.81), GLS (TAV 15.4[13.6,17.9], BAV 16.3[12.8,18.1];P=0.82. Perfusion and cardiac energetic improvements were also similar between the AS cohorts: PCr/ATP (TAV:1.96[1.68,2.26], BAV:1.96[1.79,2.13];P=0.91), stress-MBF (TAV:1.63[1.37,1.97], BAV:1.56[1.25,1.97];P=0.86), and MPR (TAV:2.64[1.91,3.26], BAV:2.55[2.07,3.28];P=0.70). Conclusions Patients with severe AS irrespective of BAV or TAV morphology, show a similar myocardial phenotype pre-AVR, with similar magnitudes of reverse remodelling post-AVR.

Cardiovascular magnetic resonance to differentiate veteran athlete's heart with cavity dilatation and mild dilated cardiomyopathy

Abstract Introduction Endurance athletic training may lead to left ventricular (LV) dilatation and mildly reduced resting LV function which can be difficult to differentiate from dilated cardiomyopathy (DCM). Myocardial fibrosis is increasingly recognised in lifelong athletes and is also prevalent in DCM where it confers adverse prognosis.(1,2) However, it is unknown whether the pattern and prevalence of fibrosis in athletes with cavity dilatation differs from DCM. In this study, we compared the CMR fibrosis distribution and tissue characteristics between athletic LV dilatation and mild DCM patients. Methods We prospectively recruited 113 males; 64 endurance athletes and 49 mild DCM patients. Inclusion criteria Age 50-80 years, LVEF 45-54% and LV end-diastolic volume indexed to body surface area (LVEDVi)≥110ml/m2. Athletes trained≥10 weekly hrs for≥15 yrs. Exclusion criteria; Chest pain, prior coronary revascularisation, severe valvular disease, myocarditis, hypertrophic cardiomyopathy, inducible ischaemia or myocardial infarction on CMR. CMR protocol included volumetric assessment, T1 mapping, quantitative stress perfusion and quantitative late gadolinium enhancement. Statistical analysis between groups was performed using unpaired t-test and receiver-operator curve (ROC) analysis. Results LVEDVi was not significantly different between athletes and mild DCM patients (123.3±12.6 vs 129.8±23.1ml/m2, P=0.057). However, LVEF (52.0±6.1 vs 47.6±5.2%, P<0.001) and right ventricular (RV) EDVi (121.0±14.3 vs 97.6±25.2ml/m2, P<0.001) were both greater in athletes. There was no difference in non-ischaemic fibrosis prevalence between both groups (50.0 vs 49.0%, P=0.915) nor the burden of fibrosis (3.5±2.9 vs 7.4±12.0g, P=0.087). However, the distribution of fibrosis varied with a significantly greater prevalence of basal mid-myocardial inferolateral fibrosis amongst athletes (87.5 vs 50.0%, P=0.002) whereas basal mid-myocardial inferoseptal fibrosis was significantly more common in mild DCM (45.8 vs 9.4%, P=0.002). Native T1 (1249.0±38.1 vs 1308.3±47.1ms, P<0.001) and extracellular volume (ECV) (22.0±2.1 vs 25.9±3.5%, P<0.001) were both lower in athletes than mild DCM patients. Furthermore, athletes had higher myocardial perfusion reserve (MPR) (3.65±1.30 vs 2.76±0.92, P<0.001) and stress myocardial blood flow (MBF) (2.09±0.70 vs 1.62±0.66, P<0.001). On ROC analysis, native T1 (area under curve (AUC) 0.89, P<0.001), ECV (AUC 0.85, P<0.001) and stress MBF (AUC 0.68, P<0.001) were able to differentiate athletes and mild DCM. Native T1 and ECV were significantly better at discriminating than MPR (P<0.001). Conclusion Myocardial fibrosis was highly prevalent in both veteran endurance athlete's heart and mild DCM whilst its distribution was distinctive between the groups. Native T1 and ECV were the best discriminators. Recognition of fibrosis patterns and associated tissue characteristics may be clinically useful to differentiate these two overlapping phenotypes.Figure 1; LGE distribution in athletes cFigure 2; CMR tissue characteristics to

Assessment of surgical revascularization completeness with quantitative myocardial blood flow distribution derived from CCTA in severe coronary artery disease

Abstract Background Complete revascularization remained the "holy grail" in the treatment of patients with severe coronary artery disease (CAD). However, there is no universally accepted definition of complete revascularization after coronary bypass graft surgery (CABG). The current assessment methods are visual, categorical, and biased by the operator's intention. Moreover, no method to date provides an individualized quantification of residual ischemia burden. Purpose We aim to provide an individualized method to assess the completeness of surgical revascularization through quantitative myocardial blood flow distribution derived from coronary computed tomography angiography (CCTA) that could reflect the actual functional ischemia burden after CABG. Methods Patients with 3VD and/or left main CAD were enrolled in the first-in-human FAST TRACK CABG trial for surgical revascularization guided solely by CCTA and fractional flow reserve derived from CCTA (FFRCT). Following CABG, the study protocol mandated a 30-day follow-up CCTA, which provides graft patency and topographical adequacy of the bypass graft anastomoses. The pre- and post-CABG CCTA were analyzed. The FFRCT value and percent myocardial blood flow distribution (%MBF) were computed for all 16 SYNTAX score segments using the validated method of Keulards et al(1). On pre-CABG CCTA, the myocardium located distal to the site where the FFRCT value dropped below 0.80 on the vessel centerline was considered ischemic, and the %MBF of the subtended myocardium was summed into the total percent ischemic myocardium (Figure 1). Following CABG, the segment was considered adequately revascularized when a non-narrowed graft was anastomosed distally to the site of FFRCT≤0.8 on the pre-operative CCTA. The change in percent ischemic myocardium and the residual ischemic burden were calculated for each patient (Figure 2). Results CCTA, FFRCT, and %MBF were obtained pre- and post-CABG in 96 patients, and the percent ischemic myocardium was computed per patient. At baseline, the average percent ischemic myocardium was 72.0(19.1)%. Post-CABG, the residual percent ischemic myocardium was 13.6(15.1)%. Residual percent ischemic myocardium <10% was achieved in 44 patients (44.8%). The first diagonal branch(n=13), distal LCX(n=12), and the first obtuse marginal branch(n=10) were the most frequent segments not revascularized, which subtended an average MBF of 12.2(3.5)%, 16.7(8.4)%, and 11.3(7.3)%, respectively. The main reason for inadequate revascularization was surgical deferral, with graft occlusion accounting for only 13.6% of the residual ischemic segments. Conclusion Percent ischemic myocardium and the completeness of surgical revascularization can be assessed with CCTA-derived %MBF. This novel method allows clinicians to assess the individualized ischemia burden and the completeness of revascularization that could be incorporated into personalized CABG planning.Figure 1Figure 2

One-year results from the REDUCER-I multi-center real-world clinical trial of the treatment of refractory angina with the coronary sinus Reducer

Abstract Background/Introduction Patients with refractory angina have chronic symptoms due to reversible ischemia which are inadequately controlled with optimal medical therapy or interventional treatments. These patients suffer from a poor quality of life and place a significant strain on the health care system due to their frequent rehospitalizations. The coronary sinus (CS) Reducer is a stainless-steel hour-glass shaped mesh stent that creates a focal narrowing in the lumen of the CS resulting in improved microvascular resistance and redistribution of myocardial blood flow. Purpose The COSIRA randomized controlled trial showed the Reducer is a safe and effective treatment for refractory angina with patients having significant improvements in Canadian Cardiovascular Society (CCS) class and other measures of quality of life. The REDUCER-I post-market study evaluated the long-term outcomes with the Reducer in a large and challenging ‘real-world’ cohort. Methods REDUCER-I is a multicenter, non-randomized study conducted across 26 medical centers in Europe. At one year, device effectiveness was assessed by improvement in CCS grade as compared to baseline and device safety was assessed by Major Adverse Cardiac Events (MACE). Secondary endpoints included six-minute walk tests, EQ-5D-5L tests, and Seattle Angina Questionnaires (SAQ). Subjects were followed at 30 days, 6 months, and annually through five years. Results The as-treated population includes a total of 371 patients who received a Reducer implant (78.7% (292/371) male, 47.2% (175/371) diabetic, 73.9% (274/371) post-revascularization). The one-year Kaplan-Meier overall MACE rate post-implant was 7.1% (95% CI [4.9, 10.4]). There were nine deaths within the first 365 days, one death was due to unknown causes and eight deaths were adjudicated to as not being device- or procedure-related. At 12 months, 70.0% (205/293) of patients improved by ≥1 CCS class. At baseline, 72.2% (232/363) of patients were CCS class III/IV and this proportion decreased to 18.1% (54/298) at 12 months (P<0.0001). The patients’ baseline six-minute walk distance was 327.5±116.1m which improved by a mean of 30.8±81.8m at 12 months (p<.0001). In the year prior to Reducer implant, 33.3% (88/264) of the patients had at least one visit to the emergency department compared to 11.7% (31/264) in the year after Reducer implant (p<.0001). The significant improvements in CCS class and SAQ-QoL were sustained through 3 years (Figure). Conclusion In this 12-month analysis of the REDUCER-I study, patients with refractory angina treated with the CS Reducer had low MACE rates and showed significant and sustained improvements in angina, QoL, functional capacity, and need for rehospitalization.

Artificial intelligence-based automated plaque quantification from CCTA to predict acute coronary syndrome on top of obstructive or ischemic coronary artery disease

Abstract Background Artificial intelligence (AI)-based quantitative computed tomography (AI-QCT) is a novel tool for automated plaque characterization and quantification from coronary computed tomography angiography (CCTA). The prognostic value of various AI-QCT plaque types on top of the presence of obstructive or ischemic coronary artery disease (CAD) is unknown. Purpose To investigate the added prognostic value for acute coronary syndrome (ACS) of AI-QCT total plaque burden (percent atheroma volume (PAV) %), and its subcomponents non-calcified plaque burden (NCPB), low-attenuation plaque burden (LAP), and calcified plaque burden (CPB) (%) on top of obstructive or ischemic CAD. Methods A cohort of 2007 symptomatic patients having undergone CCTA and selective downstream PET perfusion for suspected CAD was analyzed. Patients with prior or early elective revascularization within 6 months from CCTA were excluded. Obstructive CAD was defined as ≥1 vessel with >50% visual stenosis, and ischemic CAD as absolute hyperemic myocardial blood flow ≤2.3 ml/g/min in ≥2 adjacent segments on 15O-H2O PET. Multivariable Cox regressions adjusted for clinical confounders (age, sex hypertension, typical angina) including each plaque type separately (per 1.0%) on top of obstructive or ischemic CAD, respectively, were performed. The amount of LAP was <1% and therefore pooled together with NCPB. Results Throughout a median follow-up of 7 years, 72/2007 patients experienced ACS (50 myocardial infarction, 22 unstable angina). On top of obstructive CAD, all plaque types were independent predictors of ACS (Figure 1A), however according to the C-indexes (p-value vs. obstructive CAD), only PAV (C-index=0.814, p=0.010) and NCPB+LAP (C-index=0.818, p=0.014), but not CPB (C-index=0.800, p=0.066) significantly improved the prediction of ACS on top of obstructive CAD (C-index=0.790) (Figure 2A). On top of ischemic CAD (1967 patients, 66 events), all plaque types were also independent predictors of ACS (Figure 1B). But, similarly, according to the C-indexes (p-value vs. ischemic CAD), only PAV (C-index=0.818, p=0.003), and NCPB+LAP (C-index=0.818, p=0.005), but not CPB (C-index=0.798, p=0.054) significantly improved the prediction of ACS on top of ischemic CAD (C-index=0.776) (Figure 2B). NCPB+LAP alone performed similarly as PAV on top of obstructive (p=0.554) and ischemic CAD (p=0.991) (Figure 2). Conclusions Among patients with native coronary arteries treated medically, AI-based plaque quantification significantly improved the prediction of ACS on top of obstructive or ischemic CAD. The risk of ACS was largely related to NCPB+LAP, whereas CPB did not significantly improve risk stratification.Adjusted HR for ACS per plaque typeC-indexes for ACS

Mechanisms affecting the neutrophil to lymphocyte ratio in heart failure: a prospective CMR study

Abstract Background The neutrophil-to-lymphocyte ratio (NLR) is a simple measure of inflammation defined as the ratio of the neutrophils to lymphocytes as measured in the full blood count. It is well known that patients with heart failure (HF) have elevated levels of pro-inflammatory cytokines. It has been demonstrated in a recent meta-analysis that elevated NLR in heart failure is significantly associated with worse outcomes including all-cause mortality, heart failure readmissions and cardiovascular death. Purpose Given this association between NLR and adverse prognosis in HF, we aim to identify which factors are associated with an elevated NLR. This may help to recognise patients at higher risk and guide management. Methods Patients with newly diagnosed HF and left ventricular ejection fraction <50% on referral echocardiogram were prospectively recruited at the time of referral for cardiovascular magnetic resonance (CMR). Exclusion criteria included prior revascularisation, myocardial infarction, anginal chest pain, congenital heart disease and suspected myocarditis. In one appointment patients (N=599) underwent clinical assessment, medication review, full blood count and CMR. The CMR protocol included quantitative assessment myocardial blood flow at stress and rest, assessment of ischaemic and non-ischaemic fibrosis by late gadolinium enhancement imaging and T1 and T2 mapping. Guideline directed medical therapy was determined by the referring physician. Baseline demographic data, medication and MRI results were recorded for all patients. NLR was calculated from full blood count and split into tertiles. Clinical and CMR parameters were compared between tertiles by analysis of variance and chi squared test. Results See Table 1 The factors which were found to be significantly associated with an elevated NLR were age, atrial fibrillation, NTproBNP, diuretic dose, inducible ischaemia and ischaemic fibrosis. Of note there was no significant difference between groups in terms of guideline directed medical therapy use or other CMR parameters. Conclusion NLR is increasingly recognised as a marker of adverse risk in patients with heart failure. This prospective study of 599 heart failure patients with reduced ejection fraction has identified that an elevated NLR is associated with: 1. Evidence of congestion as evidenced by NTproBNP results and increased diuretic doses. 2. Occult coronary artery disease as shown by greater levels of inducible ischaemia and ischaemic fibrosis. These findings suggest that the adverse prognosis associated with elevated NLR in heart failure may be mediated by worsening congestion and occult coronary artery disease. Importantly there was no association between myocardial inflammation or oedema (measured as native T1 and T2) and NLR. Whether NLR improves with medical therapy of heart failure remains to be established and our findings need to be validated in more varied cohorts of patients with heart failure.