AimsWe sought to evaluate the mechanism of angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan therapy and compare it with a valsartan-only control group in patients with heart... Show moreAimsWe sought to evaluate the mechanism of angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan therapy and compare it with a valsartan-only control group in patients with heart failure with reduced ejection fraction (HFrEF).Methods and resultsThe study was a phase IV, prospective, randomized, double-blind, parallel-group study in patients with New York Heart Association class II–III heart failure and left ventricular ejection fraction (LVEF) ≤35%. During a 6-week run-in period, all patients received valsartan therapy, which was up-titrated to the highest tolerated dose level (80 mg bid or 160 mg bid) and then randomized to either valsartan or sacubitril/valsartan. Myocardial oxygen consumption, energetic efficiency of cardiac work, cardiac and systemic haemodynamics were quantified using echocardiography and 11C-acetate positron emission tomography before and after 6 weeks of therapy (on stable dose) in 55 patients (ARNI group: n = 27, mean age 63 ± 10 years, LVEF 29.2 ± 10.4%; and valsartan-only control group: n = 28, mean age 64 ± 8 years, LVEF 29.0 ± 7.3%; all p = NS). The energetic efficiency of cardiac work remained unchanged in both treatment arms. However, both diastolic (−4.5 mmHg; p = 0.026) and systolic blood pressure (−9.8 mmHg; p = 0.0007), myocardial perfusion (−0.054 ml/g/min; p = 0.045), and left ventricular mechanical work (−296; p = 0.038) decreased significantly in the ARNI group compared to the control group. Although myocardial oxygen consumption decreased in the ARNI group (−5.4%) compared with the run-in period and remained unchanged in the control group (+0.5%), the between-treatment group difference was not significant (p = 0.088).ConclusionsWe found no differences in the energetic efficiency of cardiac work between ARNI and valsartan-only groups in HFrEF patients. However, ARNI appears to have haemodynamic and cardiac mechanical effects over valsartan in heart failure patients. Show less
Kuneman, J.H.; Hoogen, I.J. van den; Schultz, J.; Maaniitty, T.; Rosendael, A.R. van; Kamperidis, V.; ... ; Knuuti, J. 2023
Background: The various plaque components have been associated with ischemia and outcomes in patients with coronary artery disease (CAD). The main goal of this analysis was to test the hypothesis... Show moreBackground: The various plaque components have been associated with ischemia and outcomes in patients with coronary artery disease (CAD). The main goal of this analysis was to test the hypothesis that, at patient level, the fraction of non-calcified plaque volume (PV) of total PV is associated with ischemia and outcomes in patients with CAD. This ratio could be a simple and clinically useful parameter, if predicting outcomes. Methods: Consecutive patients with suspected CAD undergoing coronary computed tomography angiography with selective positron emission tomography perfusion imaging were selected. Plaque components were quantitatively analyzed at patient level. The fraction of various plaque components were expressed as percentage of total PV and examined among patients with non-obstructive CAD, suspected stenosis with normal perfusion, and those with reduced myocardial perfusion. Clinical outcomes included all-cause mortality and myocardial infarction. Results: In total, 494 patients (age 63 & PLUSMN; 9 years, 55% male) were included. Total PV and all plaque components were significantly larger in patients with reduced myocardial perfusion compared to patients with normal perfusion and those with non-obstructive CAD. During follow-up 35 events occurred. Patients with any plaque component & GE; median showed worse outcomes (log-rank p < 0.001 for all). In addition, low-attenuation plaque & GE; median was associated with worse outcomes independent of total PV (adjusted HR: 2.754, 95% CI: 1.022-7.0419, p = 0.045). The fractions of the various plaque components were not associated with outcomes. Conclusion: Larger total PV or any plaque component at patient level are associated with abnormal myocardial perfusion and adverse events. The various plaque components as fraction of total PV lack additional prognostic value. Show less
AimsCombined anatomical and functional imaging enables detection of non-obstructive and obstructive coronary artery disease (CAD) as well as myocardial ischaemia. We evaluated sex differences in... Show moreAimsCombined anatomical and functional imaging enables detection of non-obstructive and obstructive coronary artery disease (CAD) as well as myocardial ischaemia. We evaluated sex differences in disease profile and outcomes after combined computed tomography angiography (CTA) and positron emission tomography (PET) perfusion imaging in patients with suspected obstructive CAD.Methods and resultsWe retrospectively evaluated 1948 patients (59% women) referred for coronary CTA due to suspected CAD during the years 2008–2016. Patients with a suspected obstructive lesion on coronary CTA (n = 657) underwent 15O-water PET to assess stress myocardial blood flow (MBF). During a mean follow-up of 6.8 years, 182 adverse events (all-cause death, myocardial infarction, or unstable angina) occurred. Women had more often normal coronary arteries (42% vs. 22%, P < 0.001) and less often abnormal stress MBF (9% vs. 28%, P < 0.001) than men. The annual adverse event rate was lower in women vs. men (1.2% vs. 1.7%, P = 0.02). Both in women and men, coronary calcification, non-obstructive CAD, and abnormal stress MBF were independent predictors of events. Abnormal stress MBF was associated with 5.0- and 5.6-fold adverse event rates in women and men, respectively. There was no interaction between sex and coronary calcification, non-obstructive CAD, or abnormal stress MBF in terms of predicting adverse events.ConclusionAmong patients evaluated for chronic chest pain, women have a lower prevalence of ischaemic CAD and a lower rate of adverse events. Combined coronary CTA and PET myocardial perfusion imaging predict outcomes equally in women and men. Show less
Background: Additional strategies are needed to refine the referral for diagnostic testing of symptomatic patients with suspected coronary artery disease (CAD). We aimed to compare various models... Show moreBackground: Additional strategies are needed to refine the referral for diagnostic testing of symptomatic patients with suspected coronary artery disease (CAD). We aimed to compare various models to predict hemodynamically obstructive CAD. Methods and results: Symptomatic patients with suspected CAD who underwent coronary artery calcium scoring (CACS) and sequential coronary computed tomography angiography (CCTA) and [O-15]H2O positron emission tomography (PET) myocardial perfusion imaging were analyzed. Obstructive CAD was defined as a suspected coronary artery stenosis on CCTA with myocardial ischemia on PET (absolute stress myocardial perfusion <= 2.4 mL/g/min in >= 1 segment). Three models were developed to predict obstructive CAD-induced myocardial ischemia using logistic regression analysis: (1) basic model: including age, sex and cardiac symptoms, (2) risk factor model: adding number of risk factors to the basic model, and (3) CACS model: adding CACS to the risk factor model. Model performance was evaluated using discriminatory ability with area under the receiver-operating characteristic curves (AUC). A total of 647 patients (mean age 62 +/- 9 years, 45% men) underwent CACS and sequential CCTA and PET myocardial perfusion imaging. Obstructive CAD with myocardial ischemia on PET was present in 151 (23%) patients. CACS was independently associated with myocardial ischemia (P < .001). AUC for the discrimination of ischemia for the CACS model was superior over the basic model and risk factor model (P < .001). Conclusions: Adding CACS to the model including age, sex, cardiac symptoms and number of risk factors increases the accuracy to predict obstructive CAD with myocardial ischemia on PET in symptomatic patients with suspected CAD. Show less
Schultz, J.; Hoogen, I.J. van den; Kuneman, J.H.; Graaf, M.A. de; Kamperidis, V.; Broersen, A.; ... ; Knuuti, J. 2022
Endothelial wall shear stress (ESS) is a biomechanical force which plays a role in the formation and evolution of atherosclerotic lesions. The purpose of this study is to evaluate coronary computed... Show moreEndothelial wall shear stress (ESS) is a biomechanical force which plays a role in the formation and evolution of atherosclerotic lesions. The purpose of this study is to evaluate coronary computed tomography angiography (CCTA)-based ESS in coronary arteries without atherosclerosis, and to assess factors affecting ESS values. CCTA images from patients with suspected coronary artery disease were analyzed to identify coronary arteries without atherosclerosis. Minimal and maximal ESS values were calculated for 3-mm segments. Factors potentially affecting ESS values were examined, including sex, lumen diameter and distance from the ostium. Segments were categorized according to lumen diameter tertiles into small (< 2.6 mm), intermediate (2.6-3.2 mm) or large (>= 3.2 mm) segments. A total of 349 normal vessels from 168 patients (mean age 59 +/- 9 years, 39% men) were included. ESS was highest in the left anterior descending artery compared to the left circumflex artery and right coronary artery (minimal ESS 2.3 Pa vs. 1.9 Pa vs. 1.6 Pa, p < 0.001 and maximal ESS 3.7 Pa vs. 3.0 Pa vs. 2.5 Pa, p < 0.001). Men had lower ESS values than women, also after adjusting for lumen diameter (p < 0.001). ESS values were highest in small segments compared to intermediate or large segments (minimal ESS 3.8 Pa vs. 1.7 Pa vs. 1.2 Pa, p < 0.001 and maximal ESS 6.0 Pa vs. 2.6 Pa vs. 2.0 Pa, p < 0.001). A weak to strong correlation was found between ESS and distance from the ostium (rho = 0.22-0.62, p < 0.001). CCTA-based ESS values increase rapidly and become widely scattered with decreasing lumen diameter. This needs to be taken into account when assessing the added value of ESS beyond lumen diameter in highly stenotic lesions. Show less
Wang, X.; Hoogen, I.J. van den; Butcher, S.C.; Kuneman, J.H.; Graaf, M.A. de; Kamperidis, V.; ... ; Bax, J.J. 2022
Aims: Coronary atherosclerosis with a large necrotic core has been postulated to reduce the vasodilatory capacity of vascular tissue. In the present analysis, we explored whether total plaque... Show moreAims: Coronary atherosclerosis with a large necrotic core has been postulated to reduce the vasodilatory capacity of vascular tissue. In the present analysis, we explored whether total plaque volume and necrotic core volume on coronary computed tomography angiography (CCTA) are independently associated with myocardial ischaemia on positron emission tomography (PET). Methods and results: From a registry of symptomatic patients with suspected coronary artery disease and clinically indicated CCTA with sequential [O-15]H2O PET myocardial perfusion imaging, we quantitatively measured diameter stenosis, total and compositional plaque volumes on CCTA. Primary endpoint was myocardial ischaemia on PET, defined as an absolute stress myocardial blood flow <= 2.4 mL/g/min in >= 1 segment. Multivariable prediction models for myocardial ischaemia were consecutively created using logistic regression analysis (stenosis model: diameter stenosis >= 50%; plaque volume model: +total plaque volume; plaque composition model: +necrotic core volume). A total of 493 patients (mean age 63 +/- 8 years, 54% men) underwent sequential CCTA/PET imaging. In 153 (31%) patients, myocardial ischaemia was detected on PET. Diameter stenosis >= 50% (P < 0.001) and necrotic core volume (P = 0.029) were independently associated with myocardial ischaemia, while total plaque volume showed borderline significance (P = 0.052). The plaque composition model (chi(2) = 169) provided incremental value for the prediction of ischaemia when compared with the stenosis model (chi(2) = 138, P < 0.001) and plaque volume model (chi(2) = 164, P = 0.021). Conclusion: The volume of necrotic core on CCTA independently and incrementally predicts myocardial ischaemia on PET, beyond diameter stenosis alone. Show less
Hoogen, I.J. van den; Schultz, J.; Kuneman, J.H.; Graaf, M.A. de; Kamperidis, V.; Broersen, A.; ... ; Knuuti, J. 2022
Aims Evolving evidence suggests that endothelial wall shear stress (ESS) plays a crucial role in the rupture and progression of coronary plaques by triggering biological signalling pathways. We... Show moreAims Evolving evidence suggests that endothelial wall shear stress (ESS) plays a crucial role in the rupture and progression of coronary plaques by triggering biological signalling pathways. We aimed to investigate the patterns of ESS across coronary lesions from non-invasive imaging with coronary computed tomography angiography (CCTA), and to define plaque-associated ESS values in patients with coronary artery disease (CAD). Methods and results: Symptomatic patients with CAD who underwent a clinically indicated CCTA scan were identified. Separate core laboratories performed blinded analysis of CCTA for anatomical and ESS features of coronary atherosclerosis. ESS was assessed using dedicated software, providing minimal and maximal ESS values for each 3 mm segment. Each coronary lesion was divided into upstream, start, minimal luminal area (MLA), end and downstream segments. Also, ESS ratios were calculated using the upstream segment as a reference. From 122 patients (mean age 64 +/- 7 years, 57% men), a total of 237 lesions were analyzed. Minimal and maximal ESS values varied across the lesions with the highest values at the MLA segment [minimal ESS 3.97 Pa (IQR 1.93-8.92 Pa) and maximal ESS 5.64 Pa (IQR 3.13-11.21 Pa), respectively]. Furthermore, minimal and maximal ESS values were positively associated with stenosis severity (P < 0.001), percent atheroma volume (P < 0.001), and lesion length (P <= 0.023) at the MLA segment. Using ESS ratios, similar associations were observed for stenosis severity and lesion length. Conclusions: Detailed behaviour of ESS across coronary lesions can be derived from routine non-invasive CCTA imaging. This may further improve risk stratification. Show less
Purpose We evaluated the value of reduced global and segmental absolute stress myocardial blood flow (sMBF) quantified by [O-15] water positron emission tomography (PET) for predicting cardiac... Show morePurpose We evaluated the value of reduced global and segmental absolute stress myocardial blood flow (sMBF) quantified by [O-15] water positron emission tomography (PET) for predicting cardiac events in patients with suspected obstructive coronary artery disease (CAD). Methods Global and segmental sMBF during adenosine stress were retrospectively quantified in 530 symptomatic patients who underwent [O-15] water PET for evaluation of coronary stenosis detected by coronary computed tomography angiography. Results Cardiovascular death, myocardial infarction, or unstable angina occurred in 28 (5.3%) patients at a 4-year follow-up. Reduced global sMBF was associated with events (area under the receiver operating characteristic curve 0.622, 95% confidence interval (95% CI) 0.538-0.707, p = 0.006). Reduced global sMBF (< 2.2 ml/g/min) was found in 22.8%, preserved global sMBF despite segmentally reduced sMBF in 35.3%, and normal sMBF in 41.9% of patients. Compared with normal sMBF, reduced global sMBF was associated with the highest risk of events (adjusted hazard ratio (HR) 6.970, 95% CI 2.271-21.396, p = 0.001), whereas segmentally reduced sMBF combined with preserved global MBF predicted an intermediate risk (adjusted HR 3.251, 95% CI 1.030-10.257, p = 0.044). The addition of global or segmental reduction of sMBF to clinical risk factors improved risk prediction (net reclassification index 0.498, 95% CI 0.118-0.879, p = 0.010, and 0.583, 95% CI 0.203-0.963, p = 0.002, respectively). Conclusion In symptomatic patients evaluated for suspected obstructive CAD, reduced global sMBF by [O-15] water PET identifies those at the highest risk of adverse cardiac events, whereas segmental reduction of sMBF with preserved global sMBF is associated with an intermediate event risk. Show less
Aims To test the hypothesis that virtual functional assessment index (vFAI) is related with regional flow parameters derived by quantitative positron emission tomography (PET) and can be used to... Show moreAims To test the hypothesis that virtual functional assessment index (vFAI) is related with regional flow parameters derived by quantitative positron emission tomography (PET) and can be used to assess abnormal vasodilating capability in coronary vessels with stenotic lesions at coronary computed tomography angiography (CCTA).Methods and results vFAI, stress myocardial blood flow (MBF), and myocardial flow reserve (MFR) were assessed in 78 patients (mean age 62.2 +/- 7.7 years) with intermediate pre-test likelihood of coronary artery disease (CAD). Coronary stenoses >= 50% were considered angiographically significant. PET was considered positive for significant CAD, when more than one contiguous segments showed stress MBF <= 2.3 mL/g/min for O-15-water or <1.79 mL/g/min for N-13-ammonia. MFR thresholds were <= 2.5 and <= 2.0, respectively. vFAI was lower in vessels with abnormal stress MBF (0.76 +/- 0.10 vs. 0.89 +/- 0.07, P < 0.001) or MFR (0.80 +/- 0.10 vs. 0.89 +/- 0.07, P < 0.001). vFAI had an accuracy of 78.6% and 75% in unmasking abnormal stress MBF and MFR in O-15-water and 82.7% and 71.2% in N-13-ammonia studies, respectively. Addition of vFAI to anatomical CCTA data increased the ability for predicting abnormal stress MBF and MFR in O-15-water studies [AUC(ccta+vfai) = 0.866, 95% confidence interval (CI) 0.783-0.949; P = 0.013 and AUC(ccta+vfai) = 0.737, 95% CI 0.648-0.825; P = 0.007, respectively]. An incremental value was also demonstrated for prediction of stress MBF (AUC(ccta+vfai) = 0.887, 95% CI 0.799-0.974; P = 0.001) in N-13-ammonia studies. A similar trend was recorded for MFR (AUC(ccta+vfai) = 0.780, 95% CI 0.632-0.929; P = 0.13).Conclusion vFAI identifies accurately the presence of impaired vasodilating capability. In combination with anatomical data, vFAI enhances the diagnostic performance of CCTA. Show less
ObjectivesApplication of computational fluid dynamics (CFD) to three-dimensional CTCA datasets has been shown to provide accurate assessment of the hemodynamic significance of a coronary lesion. We... Show moreObjectivesApplication of computational fluid dynamics (CFD) to three-dimensional CTCA datasets has been shown to provide accurate assessment of the hemodynamic significance of a coronary lesion. We aim to test the feasibility of calculating a novel CTCA-based virtual functional assessment index (vFAI) of coronary stenoses >30% and 90% by using an automated in-house-developed software and to evaluate its efficacy as compared to the invasively measured fractional flow reserve (FFR).Methods and resultsIn 63 patients with chest pain symptoms and intermediate (20-90%) pre-test likelihood of coronary artery disease undergoing CTCA and invasive coronary angiography with FFR measurement, vFAI calculations were performed after 3D reconstruction of the coronary vessels and flow simulations using the finite element method. A total of 74 vessels were analyzed. Mean CTCA processing time was 25(10)min. There was a strong correlation between vFAI and FFR, (R=0.93, p<0.001) and a very good agreement between the two parameters by the Bland-Altman method of analysis. The mean difference of measurements from the two methods was 0.03 (SD=0.033), indicating a small systematic overestimation of the FFR by vFAI. Using a receiver-operating characteristic curve analysis, the optimal vFAI cutoff value for identifying an FFR threshold of 0.8 was 0.82 (95% CI 0.81 to 0.88).ConclusionsvFAI can be effectively derived from the application of computational fluid dynamics to three-dimensional CTCA datasets. In patients with coronary stenosis severity >30% and 90%, vFAI performs well against FFR and may efficiently distinguish between hemodynamically significant from non-significant lesions.Key PointsVirtual functional assessment index (vFAI) can be effectively derived from 3D CTCA datasets.In patients with coronary stenoses severity >30% and 90%, vFAI performs well against FFR. vFAI may efficiently distinguish between functionally significant from non-significant lesions. Show less
Dimitriu-Leen, A.C.; Rosendael, A.R. van; Smit, J.M.; Elst, T. van; Geloven, N. van; Maaniitty, T.; ... ; Bax, J.J. 2017
