Introduction: Despite optimal treatment, patients with chronic coronary artery disease (CAD) and ... more Introduction: Despite optimal treatment, patients with chronic coronary artery disease (CAD) and diabetes mellitus (DM) are at high risk of cardiovascular events, emphasizing the need for new treatment options. The Low-Dose Colchicine 2 (LoDoCo2) trial demonstrated that colchicine reduces cardiovascular risk in patients with chronic CAD. This analysis determines the efficacy of colchicine in patients with chronic CAD and DM as well as the effect of colchicine on the development of new-onset type 2 diabetes mellitus (T2DM). Methods: The LoDoCo2 trial randomized 5,522 patients to placebo or colchicine 0.5 mg once daily, with a median follow-up of 28.6 months. The primary composite endpoint was cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven revascularization. The effect of its treatment in patients with and without DM was evaluated by including an interaction term in the model. Results: A total of 1,007 participants (18.2%) had T2DM at baseline. The adjusted hazard ratio (HR) [(95% confidence interval (CI)] for the primary endpoint in the T2DM group was 1.52 (1.15-2.01, p < 0.01) compared with the group without T2DM. The HR for the treatment effect on the primary endpoint was 0.87 (0.61-1.25) in participants with T2DM and 0.64 (0.51-0.80) in participants without diabetes (p interaction = 0.14). The incidence of new-onset T2DM was 1.5% (34 out of 2,270) in the colchicine group and 2.2% (49 out of 2,245) in the placebo group (p = 0.10). Discussion: In conclusion, based on the current evidence, the beneficial effects of colchicine on cardiovascular endpoints are consistent regardless of DM status. The potential benefits of colchicine in preventing new-onset DM need further investigation. These findings are only hypothesis-generating and require larger prospective trials to confirm the results.
Patients with coronary disease remain at high risk for future cardiovascular events, even with op... more Patients with coronary disease remain at high risk for future cardiovascular events, even with optimal risk factor modification, lipid-lowering drugs and antithrombotic regimens. A myriad of inflammatory pathways contribute to progression of the atherosclerotic burden in these patients. Only in the last few years has the inflammatory biology of atherosclerosis translated into clinical therapeutic options. Low-dose colchicine can provide a clinically relevant reduction in the risk for composite and individual major cardiovascular outcomes in patients with acute and chronic coronary syndromes. Among others, its anti-inflammatory effects in atherosclerosis seem to be related to neutrophil recruitment and adhesion, inflammasome inhibition, and morphological changes in platelets and platelet aggregation. Future research is aimed at further elucidating its particular mechanism of action, as well as identifying patients with the highest expected benefit and evaluating efficacy in other vas...
Background Low-dose colchicine reduces the risk of cardiovascular events in patients with chronic... more Background Low-dose colchicine reduces the risk of cardiovascular events in patients with chronic coronary artery disease (CAD), but the absolute benefit may vary between patients. Individual benefit from preventive therapies can be estimated using the guideline-recommended SMART-REACH model. Purpose This study aimed to assess the range of individual absolute 10-year and lifetime benefit from low-dose colchicine according to patient risk profile. Methods The SMART-REACH model was combined with the relative treatment effect of low-dose colchicine, and applied to all participants from the LoDoCo2 trial (n=5,522), and patients with chronic CAD from the UCC-SMART cohort (n=5,308). Individual treatment benefit was expressed as (i) 10-year absolute risk reductions (ARRs) for myocardial infarction, ischemic stroke, or cardiovascular death (MACE), and (ii) life-years gained free of MACE. Predictions were also performed for MACE plus ischemia-driven coronary revascularization (MACE+), throug...
Background: Oral activated factor XI (FXIa) inhibitors may modulate coagulation to prevent thromb... more Background: Oral activated factor XI (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without substantially increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI). Methods: We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6 to 12 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on FXIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing ...
Introduction: We evaluated international variations in management and clinical outcome for patien... more Introduction: We evaluated international variations in management and clinical outcome for patients with type 2 diabetes and heart failure (HF) by region in the Trial Evaluating Cardiovascular Outc...
Journal of the American College of Cardiology, Jan 18, 2017
The ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes) trial compared ... more The ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes) trial compared early invasive strategy with a selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and an elevated cardiac troponin T. No long-term benefit of an early invasive strategy was found at 1 and 5 years. The aim of this study was to determine the 10-year clinical outcomes of an early invasive strategy versus a selective invasive strategy in patients with NSTE-ACS and an elevated cardiac troponin T. The ICTUS trial was a multicenter, randomized controlled clinical trial that included 1,200 patients with NSTE-ACS and an elevated cardiac troponin T. Enrollment was from July 2001 to August 2003. We collected 10-year follow-up of death, myocardial infarction (MI), and revascularization through the Dutch population registry, patient phone calls, general practitioners, and hospital records. The primary outcome was the 10-year composite of death or ...
Journal of the American College of Cardiology, 2012
Background: The TRACER trial compared vorapaxar, a novel oral PAR-1 antagonist, with placebo, as ... more Background: The TRACER trial compared vorapaxar, a novel oral PAR-1 antagonist, with placebo, as add-on therapy to standard of care, among 12944 NSTE ACS patients who were predominantly treated with aspirin and clopidogrel. While vorapaxar was associated with a significant increase in major bleeding in the overall population, a lower bleeding hazard was observed in those without concomitant clopidogrel. Methods: A substudy evaluated biologic parameters including platelet reactivity in the placebo and vorapaxar arms (n=249). Platelet aggregation (PA) in response to 20μM ADP, 15μM TRAP, and CAT (2.5μg/ml collagen related peptide + 5μM ADP + 15μM TRAP)), and P2Y12 signaling using the VASP assay were measured. Results were evaluated at baseline and at 1 mo. Onset of PAR-1 inhibition was evaluated by TRAP PA at 30 min, 1, 2, and 4 hr post loading dose. Results: At 1 mo TRAP PA was strongly inhibited by vorapaxar with all subjects having < 20% PA within 2-4 hr. ADP maximal and final (5 min post agonist) PA trended lower in the vorapaxar group vs placebo whereas CAT maximal and final PA were significantly lower in the vorapaxar arm. VASP Platelet Reactivity Index (PRI) was significantly lower in both treatment arms.
Objective To determine the long-term prognostic value of stress imaging and clinical risk scoring... more Objective To determine the long-term prognostic value of stress imaging and clinical risk scoring for cardiovascular mortality in chest pain patients after ruling out acute coronary syndrome (ACS). Methods A standard rule-out protocol was performed in emergency room patients with a normal or non-diagnostic admission electrocardiogram (ECG) within 6 h of chest pain onset. ACS patients were identified by troponin T, recurrent angina and serial ECG. Dobutamine stress echocardiography (DSE) was performed after ACS was ruled out. Myocardial perfusion scintigraphy (MPS) was performed within 6 months in an outpatient setting according to the physician's discretion. Results 524 patients were included. GRACE and TIMI risk scores were 75 (57-96) and 1 (0-2) in the rule-out ACS group, and 89 (74-107) and 2 (1-3) in the ACS group, respectively (median, interquartile range). Follow-up (median 9.4 (8.9-10.0) years) was complete in 96%. 350 of 379 rule-out ACS patients had an interpretable DSE and 52 patients underwent an MPS. 21 of the rule-out ACS patients (6%) died of a cardiovascular cause compared with 24 (17%) ACS patients (p<0.001). For rule-out ACS patients, C-statistics were 0.829 and 0.803 for the GRACE and TIMI scores. In these patients, DSE and MPS outcome did not predict long-term cardiovascular mortality. In multivariate analysis, known chronic heart failure, ACE inhibitor use, and GRACE score were independent predictors of cardiovascular mortality. Conclusions TIMI and GRACE score but not DSE and MPS are accurate predictors of long-term cardiovascular mortality, even in chest pain patients with a normal or non-diagnostic electrocardiogram undergoing a rule-out protocol.
Introduction Blood biomarkers have the potential to monitor the severity of chronic heart failure... more Introduction Blood biomarkers have the potential to monitor the severity of chronic heart failure (CHF). Studies correlating repeated measurements of blood biomarkers with repeatedly assessed New York Heart Association (NYHA) class over a prolonged follow-up period, and concomitantly investigating their associations with clinical endpoints, have not yet been performed. Methods Between 2011-2013, 263 CHF patients were included. At inclusion and subsequently every 3 months, we measured N-terminal pro-B-type natriuretic (NT-proBNP), high-sensitivity troponin T (Hs-TnT) and C-reactive protein (CRP), and assessed NYHA class. The primary endpoint comprised heart failure hospitalisation, cardiovascular mortality, cardiac transplantation or left ventricular assist device implantation. Time-dependent Cox models were used. Results Mean age was 67 ± 13 years, 72% were men and 27% were in NYHA class III-IV. We obtained 886 repeated measures (median 3 [IQR 2-5] per patient). The primary endpoint was reached in 41 patients during a median follow-up of 1.0 [0.6-1.4] year. Repeatedly measured NT-proBNP and Hs-TnT were significantly associated with repeatedly assessed NYHA class, whereas CRP was not (NT-proBNP: β [95%
Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Background: Septal midwall late gadolinium enhancement (LGE) on cardiac magnetic resonance imagin... more Background: Septal midwall late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is a characteristic finding in nonischemic dilated cardiomyopathy (DCM) and is associated with adverse cardiac events. QRS-prolongation in DCM is also frequently present and a predictor of arrhythmic events and mortality. Since the His-Purkinje fibres are located in the interventricular septum, QRSprolongation may directly result from septal fibrosis, visualized by LGE. Our aim was to study the correlation of the presence and extent of septal midwall LGE and QRS-duration. Methods: DCM-patients with left ventricular (LV) dysfunction (LVEF < 50%) were included. LV volumes, systolic function and nonischemic septal midwall LGE, defined as patchy or stripe-like LGE in the septal segments, were quantified. QRS-duration on standard 12-lead ECG was measured. Results: 165 DCM-patients were included (62% male, mean age 59 ± 15 years) with a median LVEF of 36% [24-44]. Fifty-one patients (31%) demonstrated septal midwall LGE with a median extent of 8.1 gram [4.3-16.8]. Patients with midwall LGE had increased LV end-diastolic volumes (EDV) 248 mL [193-301] vs. 193 mL [160-239], p < 0.001) and lower LVEF (26% [18-35] vs. 40% [32-45], p < 0.001). Median QRS-duration was 110 ms [95-146] without a correlation to the presence nor extent of midwall LGE. QRS-duration was moderately correlated with LV-dilation and mass (respectively r = 0.35, p < 0.001 and r = 0.30, p < 0.001). Conclusion: In DCM-patients, QRS-prolongation and septal midwall LGE are frequently present and often co-exist. However, they are not correlated. This suggests that the assessment of LGE-CMR has complementary value to ECG evaluation in the clinical assessment and risk stratification of DCM-patients.
Serially measured circulating miR-22-3p is a biomarker for adverse clinical outcome in patients w... more Serially measured circulating miR-22-3p is a biomarker for adverse clinical outcome in patients with chronic heart failure van Boven,
Journal of the American College of Cardiology, 1996
We attempted to clarify the influence of coronary microvascular dysfunction on left vantdcular co... more We attempted to clarify the influence of coronary microvascular dysfunction on left vantdcular contractile response to dobutamine (DOB) administration in 12 patients with dilated cardiomyopathy (DCM) using DOB stress 201 thallium-SPECT (DOB-TI) and myocardial contrast echocardiography(MCE). Methods: 1) The echocardiographic assessment of left ventricular contractility was done by contedine method before and after DOB(10F) administration at mfd-papillary muscle level. 2) MCE: The sonicated 5=/0 human serum albumin (2 ml) was injected into left coronary artery, and the background subtracted peak intensity (API) and the washout half-time 0"1/2) of contrast enhancement were measured at the same level. 3) DOB-TI (DOB: 10),) .' 1"1 uptake was scored from 0 (defect) to 3 (normal). Total TI uptake score of left venfdcle in which was divided into 9 segments was calculated before and after DOB infusion. Results: 1) The contractility responded normally to DOB in 7 of 12 patients (Group 1). The remaining 5 patients (Group 2) showed impairment of response to DOB, However, no significant difference was found between the 2 groups in left vehicular contractility before DOB infusion. 2) MCE: The higher ApI and the shorter T1/2 were observed in Group 1 compared with those in Group 2 (p < 0.01). 3) TI uptake scorn immediately after DOB stress was significantly lower in Group 2 than in Group 1(22 ± 4 vs. 16 =1: > 0.01). TI uptake scorn did not differ between the 2 groups before DOB infusion. Conclusion: These results suggest that myocardial ischemia based on microvascular dysfunction is involved in reduced response to cathecholamine in DCM.
Journal of the American College of Cardiology, 1996
161 patients with coronary artery disease and regional wall motion (RWM) abnormalities (EF 44 ± 1... more 161 patients with coronary artery disease and regional wall motion (RWM) abnormalities (EF 44 ± 15%) who undenNent viability imaging using Tc-99m sastamibi scintigrabhy and PET with FDG were followed for 29-4-6 (22-44) months. The target region for viability imaging in each patient was categorized as predominantly scar (grOup A, n = 90), viable but not compromised (B, n = 26), or ischemically jeopardized myocardium ((3, n = 45) in regions considered for revaScularization. 63/90 patients in group A were treated medically (group A1), and 27 were revascularized (A2). Revascularization in group B and C was performed in 81% (B2) and 80% (C2). Cardiac (CE) events during follow-up were defined as cardiac death, infarction, late revascularization, or resuscitation. Improvement of angina pectods according to the C.C.Sclassification (CCS+) at foUow-up was defined as change >_. 1 grade. RWM was analyzed sedally using the centerline method in 65/84 patients with coronary revascularization and follow-up angiography after 6 4-1 months. A-RWM represents the change of RWM from baseline to follow-up angiography expressed in SD of a normal reference population.
We studied hemodynamic changes, catecholamine responses, and the occurrence of improved wall thic... more We studied hemodynamic changes, catecholamine responses, and the occurrence of improved wall thickening by echocardiography during two different dobutamineinfusion protocols. Fortythree patients were studied by using a stepwise incremental dobutamine doseinfusion protocol (1040 µg/kg/min, 3 min intervals); a subgroup of 11 patients also underwent a continuous dobutamineinfusion protocol (10 µg/kg/min for 12 min) in random order. No patient used [beta]blockers. At 3min intervals, blood pressure, heart rate, and plasma concentrations of dobutamine, epinephrine, and norepinephrine were measured. The echocardiographic improvement of wall thickening was analyzed only in paired protocols by visual assessment in left ventricular regions with normal wall motion at rest. The mean heart rate increased in the continuous and stepwise protocols from 73 to 99 and 74 to 132 beats/min. There was no significant change in blood pressure response between the two protocols. The mean plasma dobutamine concentrations during the continuous and stepwise protocols at 0, 3, 6, 9, and 12 min were 0/0; 31/38; 80/203; 106/448; and 120/692 ng/ml, respectively. In each patient, a response curve was constructed for the plasma dobutamine concentration versus heart rate. The heart rate increment and dobutamine concentration at which wall thickening was detected were similar with both protocols (14 ± 5 vs. 12 ± 7 beats/min) and (80 ± 40 vs. 92 ± 48 ng/ml; mean ± SD). Wall thickening was noted in two of 11 patients between 0 and 3 min and 11 of 11 patients between 3 and 6 min in both protocols. Catecholamine responses during the continuous and stepwise protocols were epinephrine, 23 versus 28/28 versus 36, and norepinephrine 301 versus 323/347 versus 519. Only norepinephrine plasma concentrations increased significantly during the stepwise protocol. A 6min dobutamine infusion was sufficient during both protocols to reach an adequate plasma dobutamine concentration, which induced a detectable increase of wall thickening in all patients. There is a significant differences between the two protocols with regard to the plasma catecholamine changes, so some of the hemodynamic effects during the stepwise dobutamineinfusion protocol may be mediated through release of endogenous catecholamines.
The aim of the study was to compare the extent and severity of reversible underperfusion in silen... more The aim of the study was to compare the extent and severity of reversible underperfusion in silent versus painful myocardial ischaemia during the dobutamine stress test. A consecutive series of 85 patients with significant coronary artery disease and reversible perfusion defects on technetium-99m methoxyisobutylisonitrile single-photon emission tomography performed at rest and during high-dose dobutamine stress (up to 40 gg kg q min 1) were studied. The left ventricle was divided into six segments. An ischaemic perfusion score was derived quantitatively by subtracting the rest from the stress defect score. Patients with multivessel disease had a higher ischaemic score (610_762 vs 310_411, P<0.05) and a higher number of reversible perfusion defects (2.1_+1.2 vs 1.1_+0.8, P<0.01) than patients with singlevessel disease. Typical angina occurred in 37 patients (44%) during the test. There was no significant difference between patients with and patients without angina with respect to age, gender, peak rate-pressure product, prevalence of previous myocardial infarction, diabetes mellitus, multivessel disease or number of stenotic coronary arteries. Stress, rest and ischaemic scores as well as the number and distribution of reversible defects were not different in patients with and patients without angina. Patients with angina more frequently had a history of typical angina before the test (43% vs 17%, P<0.01) and ST-segment depression during the test (54% vs 25%, P<0.01). It is concluded that in patients with coronary artery disease and ischaemia detected by dobutamine scintigraphy, the extent and severity of coronary artery disease and myocardial perfusion abnormalities are similar with or without angina during stress testing.
Introduction: Despite optimal treatment, patients with chronic coronary artery disease (CAD) and ... more Introduction: Despite optimal treatment, patients with chronic coronary artery disease (CAD) and diabetes mellitus (DM) are at high risk of cardiovascular events, emphasizing the need for new treatment options. The Low-Dose Colchicine 2 (LoDoCo2) trial demonstrated that colchicine reduces cardiovascular risk in patients with chronic CAD. This analysis determines the efficacy of colchicine in patients with chronic CAD and DM as well as the effect of colchicine on the development of new-onset type 2 diabetes mellitus (T2DM). Methods: The LoDoCo2 trial randomized 5,522 patients to placebo or colchicine 0.5 mg once daily, with a median follow-up of 28.6 months. The primary composite endpoint was cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven revascularization. The effect of its treatment in patients with and without DM was evaluated by including an interaction term in the model. Results: A total of 1,007 participants (18.2%) had T2DM at baseline. The adjusted hazard ratio (HR) [(95% confidence interval (CI)] for the primary endpoint in the T2DM group was 1.52 (1.15-2.01, p < 0.01) compared with the group without T2DM. The HR for the treatment effect on the primary endpoint was 0.87 (0.61-1.25) in participants with T2DM and 0.64 (0.51-0.80) in participants without diabetes (p interaction = 0.14). The incidence of new-onset T2DM was 1.5% (34 out of 2,270) in the colchicine group and 2.2% (49 out of 2,245) in the placebo group (p = 0.10). Discussion: In conclusion, based on the current evidence, the beneficial effects of colchicine on cardiovascular endpoints are consistent regardless of DM status. The potential benefits of colchicine in preventing new-onset DM need further investigation. These findings are only hypothesis-generating and require larger prospective trials to confirm the results.
Patients with coronary disease remain at high risk for future cardiovascular events, even with op... more Patients with coronary disease remain at high risk for future cardiovascular events, even with optimal risk factor modification, lipid-lowering drugs and antithrombotic regimens. A myriad of inflammatory pathways contribute to progression of the atherosclerotic burden in these patients. Only in the last few years has the inflammatory biology of atherosclerosis translated into clinical therapeutic options. Low-dose colchicine can provide a clinically relevant reduction in the risk for composite and individual major cardiovascular outcomes in patients with acute and chronic coronary syndromes. Among others, its anti-inflammatory effects in atherosclerosis seem to be related to neutrophil recruitment and adhesion, inflammasome inhibition, and morphological changes in platelets and platelet aggregation. Future research is aimed at further elucidating its particular mechanism of action, as well as identifying patients with the highest expected benefit and evaluating efficacy in other vas...
Background Low-dose colchicine reduces the risk of cardiovascular events in patients with chronic... more Background Low-dose colchicine reduces the risk of cardiovascular events in patients with chronic coronary artery disease (CAD), but the absolute benefit may vary between patients. Individual benefit from preventive therapies can be estimated using the guideline-recommended SMART-REACH model. Purpose This study aimed to assess the range of individual absolute 10-year and lifetime benefit from low-dose colchicine according to patient risk profile. Methods The SMART-REACH model was combined with the relative treatment effect of low-dose colchicine, and applied to all participants from the LoDoCo2 trial (n=5,522), and patients with chronic CAD from the UCC-SMART cohort (n=5,308). Individual treatment benefit was expressed as (i) 10-year absolute risk reductions (ARRs) for myocardial infarction, ischemic stroke, or cardiovascular death (MACE), and (ii) life-years gained free of MACE. Predictions were also performed for MACE plus ischemia-driven coronary revascularization (MACE+), throug...
Background: Oral activated factor XI (FXIa) inhibitors may modulate coagulation to prevent thromb... more Background: Oral activated factor XI (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without substantially increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI). Methods: We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6 to 12 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on FXIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing ...
Introduction: We evaluated international variations in management and clinical outcome for patien... more Introduction: We evaluated international variations in management and clinical outcome for patients with type 2 diabetes and heart failure (HF) by region in the Trial Evaluating Cardiovascular Outc...
Journal of the American College of Cardiology, Jan 18, 2017
The ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes) trial compared ... more The ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes) trial compared early invasive strategy with a selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and an elevated cardiac troponin T. No long-term benefit of an early invasive strategy was found at 1 and 5 years. The aim of this study was to determine the 10-year clinical outcomes of an early invasive strategy versus a selective invasive strategy in patients with NSTE-ACS and an elevated cardiac troponin T. The ICTUS trial was a multicenter, randomized controlled clinical trial that included 1,200 patients with NSTE-ACS and an elevated cardiac troponin T. Enrollment was from July 2001 to August 2003. We collected 10-year follow-up of death, myocardial infarction (MI), and revascularization through the Dutch population registry, patient phone calls, general practitioners, and hospital records. The primary outcome was the 10-year composite of death or ...
Journal of the American College of Cardiology, 2012
Background: The TRACER trial compared vorapaxar, a novel oral PAR-1 antagonist, with placebo, as ... more Background: The TRACER trial compared vorapaxar, a novel oral PAR-1 antagonist, with placebo, as add-on therapy to standard of care, among 12944 NSTE ACS patients who were predominantly treated with aspirin and clopidogrel. While vorapaxar was associated with a significant increase in major bleeding in the overall population, a lower bleeding hazard was observed in those without concomitant clopidogrel. Methods: A substudy evaluated biologic parameters including platelet reactivity in the placebo and vorapaxar arms (n=249). Platelet aggregation (PA) in response to 20μM ADP, 15μM TRAP, and CAT (2.5μg/ml collagen related peptide + 5μM ADP + 15μM TRAP)), and P2Y12 signaling using the VASP assay were measured. Results were evaluated at baseline and at 1 mo. Onset of PAR-1 inhibition was evaluated by TRAP PA at 30 min, 1, 2, and 4 hr post loading dose. Results: At 1 mo TRAP PA was strongly inhibited by vorapaxar with all subjects having < 20% PA within 2-4 hr. ADP maximal and final (5 min post agonist) PA trended lower in the vorapaxar group vs placebo whereas CAT maximal and final PA were significantly lower in the vorapaxar arm. VASP Platelet Reactivity Index (PRI) was significantly lower in both treatment arms.
Objective To determine the long-term prognostic value of stress imaging and clinical risk scoring... more Objective To determine the long-term prognostic value of stress imaging and clinical risk scoring for cardiovascular mortality in chest pain patients after ruling out acute coronary syndrome (ACS). Methods A standard rule-out protocol was performed in emergency room patients with a normal or non-diagnostic admission electrocardiogram (ECG) within 6 h of chest pain onset. ACS patients were identified by troponin T, recurrent angina and serial ECG. Dobutamine stress echocardiography (DSE) was performed after ACS was ruled out. Myocardial perfusion scintigraphy (MPS) was performed within 6 months in an outpatient setting according to the physician's discretion. Results 524 patients were included. GRACE and TIMI risk scores were 75 (57-96) and 1 (0-2) in the rule-out ACS group, and 89 (74-107) and 2 (1-3) in the ACS group, respectively (median, interquartile range). Follow-up (median 9.4 (8.9-10.0) years) was complete in 96%. 350 of 379 rule-out ACS patients had an interpretable DSE and 52 patients underwent an MPS. 21 of the rule-out ACS patients (6%) died of a cardiovascular cause compared with 24 (17%) ACS patients (p<0.001). For rule-out ACS patients, C-statistics were 0.829 and 0.803 for the GRACE and TIMI scores. In these patients, DSE and MPS outcome did not predict long-term cardiovascular mortality. In multivariate analysis, known chronic heart failure, ACE inhibitor use, and GRACE score were independent predictors of cardiovascular mortality. Conclusions TIMI and GRACE score but not DSE and MPS are accurate predictors of long-term cardiovascular mortality, even in chest pain patients with a normal or non-diagnostic electrocardiogram undergoing a rule-out protocol.
Introduction Blood biomarkers have the potential to monitor the severity of chronic heart failure... more Introduction Blood biomarkers have the potential to monitor the severity of chronic heart failure (CHF). Studies correlating repeated measurements of blood biomarkers with repeatedly assessed New York Heart Association (NYHA) class over a prolonged follow-up period, and concomitantly investigating their associations with clinical endpoints, have not yet been performed. Methods Between 2011-2013, 263 CHF patients were included. At inclusion and subsequently every 3 months, we measured N-terminal pro-B-type natriuretic (NT-proBNP), high-sensitivity troponin T (Hs-TnT) and C-reactive protein (CRP), and assessed NYHA class. The primary endpoint comprised heart failure hospitalisation, cardiovascular mortality, cardiac transplantation or left ventricular assist device implantation. Time-dependent Cox models were used. Results Mean age was 67 ± 13 years, 72% were men and 27% were in NYHA class III-IV. We obtained 886 repeated measures (median 3 [IQR 2-5] per patient). The primary endpoint was reached in 41 patients during a median follow-up of 1.0 [0.6-1.4] year. Repeatedly measured NT-proBNP and Hs-TnT were significantly associated with repeatedly assessed NYHA class, whereas CRP was not (NT-proBNP: β [95%
Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
Background: Septal midwall late gadolinium enhancement (LGE) on cardiac magnetic resonance imagin... more Background: Septal midwall late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is a characteristic finding in nonischemic dilated cardiomyopathy (DCM) and is associated with adverse cardiac events. QRS-prolongation in DCM is also frequently present and a predictor of arrhythmic events and mortality. Since the His-Purkinje fibres are located in the interventricular septum, QRSprolongation may directly result from septal fibrosis, visualized by LGE. Our aim was to study the correlation of the presence and extent of septal midwall LGE and QRS-duration. Methods: DCM-patients with left ventricular (LV) dysfunction (LVEF < 50%) were included. LV volumes, systolic function and nonischemic septal midwall LGE, defined as patchy or stripe-like LGE in the septal segments, were quantified. QRS-duration on standard 12-lead ECG was measured. Results: 165 DCM-patients were included (62% male, mean age 59 ± 15 years) with a median LVEF of 36% [24-44]. Fifty-one patients (31%) demonstrated septal midwall LGE with a median extent of 8.1 gram [4.3-16.8]. Patients with midwall LGE had increased LV end-diastolic volumes (EDV) 248 mL [193-301] vs. 193 mL [160-239], p < 0.001) and lower LVEF (26% [18-35] vs. 40% [32-45], p < 0.001). Median QRS-duration was 110 ms [95-146] without a correlation to the presence nor extent of midwall LGE. QRS-duration was moderately correlated with LV-dilation and mass (respectively r = 0.35, p < 0.001 and r = 0.30, p < 0.001). Conclusion: In DCM-patients, QRS-prolongation and septal midwall LGE are frequently present and often co-exist. However, they are not correlated. This suggests that the assessment of LGE-CMR has complementary value to ECG evaluation in the clinical assessment and risk stratification of DCM-patients.
Serially measured circulating miR-22-3p is a biomarker for adverse clinical outcome in patients w... more Serially measured circulating miR-22-3p is a biomarker for adverse clinical outcome in patients with chronic heart failure van Boven,
Journal of the American College of Cardiology, 1996
We attempted to clarify the influence of coronary microvascular dysfunction on left vantdcular co... more We attempted to clarify the influence of coronary microvascular dysfunction on left vantdcular contractile response to dobutamine (DOB) administration in 12 patients with dilated cardiomyopathy (DCM) using DOB stress 201 thallium-SPECT (DOB-TI) and myocardial contrast echocardiography(MCE). Methods: 1) The echocardiographic assessment of left ventricular contractility was done by contedine method before and after DOB(10F) administration at mfd-papillary muscle level. 2) MCE: The sonicated 5=/0 human serum albumin (2 ml) was injected into left coronary artery, and the background subtracted peak intensity (API) and the washout half-time 0"1/2) of contrast enhancement were measured at the same level. 3) DOB-TI (DOB: 10),) .' 1"1 uptake was scored from 0 (defect) to 3 (normal). Total TI uptake score of left venfdcle in which was divided into 9 segments was calculated before and after DOB infusion. Results: 1) The contractility responded normally to DOB in 7 of 12 patients (Group 1). The remaining 5 patients (Group 2) showed impairment of response to DOB, However, no significant difference was found between the 2 groups in left vehicular contractility before DOB infusion. 2) MCE: The higher ApI and the shorter T1/2 were observed in Group 1 compared with those in Group 2 (p < 0.01). 3) TI uptake scorn immediately after DOB stress was significantly lower in Group 2 than in Group 1(22 ± 4 vs. 16 =1: > 0.01). TI uptake scorn did not differ between the 2 groups before DOB infusion. Conclusion: These results suggest that myocardial ischemia based on microvascular dysfunction is involved in reduced response to cathecholamine in DCM.
Journal of the American College of Cardiology, 1996
161 patients with coronary artery disease and regional wall motion (RWM) abnormalities (EF 44 ± 1... more 161 patients with coronary artery disease and regional wall motion (RWM) abnormalities (EF 44 ± 15%) who undenNent viability imaging using Tc-99m sastamibi scintigrabhy and PET with FDG were followed for 29-4-6 (22-44) months. The target region for viability imaging in each patient was categorized as predominantly scar (grOup A, n = 90), viable but not compromised (B, n = 26), or ischemically jeopardized myocardium ((3, n = 45) in regions considered for revaScularization. 63/90 patients in group A were treated medically (group A1), and 27 were revascularized (A2). Revascularization in group B and C was performed in 81% (B2) and 80% (C2). Cardiac (CE) events during follow-up were defined as cardiac death, infarction, late revascularization, or resuscitation. Improvement of angina pectods according to the C.C.Sclassification (CCS+) at foUow-up was defined as change >_. 1 grade. RWM was analyzed sedally using the centerline method in 65/84 patients with coronary revascularization and follow-up angiography after 6 4-1 months. A-RWM represents the change of RWM from baseline to follow-up angiography expressed in SD of a normal reference population.
We studied hemodynamic changes, catecholamine responses, and the occurrence of improved wall thic... more We studied hemodynamic changes, catecholamine responses, and the occurrence of improved wall thickening by echocardiography during two different dobutamineinfusion protocols. Fortythree patients were studied by using a stepwise incremental dobutamine doseinfusion protocol (1040 µg/kg/min, 3 min intervals); a subgroup of 11 patients also underwent a continuous dobutamineinfusion protocol (10 µg/kg/min for 12 min) in random order. No patient used [beta]blockers. At 3min intervals, blood pressure, heart rate, and plasma concentrations of dobutamine, epinephrine, and norepinephrine were measured. The echocardiographic improvement of wall thickening was analyzed only in paired protocols by visual assessment in left ventricular regions with normal wall motion at rest. The mean heart rate increased in the continuous and stepwise protocols from 73 to 99 and 74 to 132 beats/min. There was no significant change in blood pressure response between the two protocols. The mean plasma dobutamine concentrations during the continuous and stepwise protocols at 0, 3, 6, 9, and 12 min were 0/0; 31/38; 80/203; 106/448; and 120/692 ng/ml, respectively. In each patient, a response curve was constructed for the plasma dobutamine concentration versus heart rate. The heart rate increment and dobutamine concentration at which wall thickening was detected were similar with both protocols (14 ± 5 vs. 12 ± 7 beats/min) and (80 ± 40 vs. 92 ± 48 ng/ml; mean ± SD). Wall thickening was noted in two of 11 patients between 0 and 3 min and 11 of 11 patients between 3 and 6 min in both protocols. Catecholamine responses during the continuous and stepwise protocols were epinephrine, 23 versus 28/28 versus 36, and norepinephrine 301 versus 323/347 versus 519. Only norepinephrine plasma concentrations increased significantly during the stepwise protocol. A 6min dobutamine infusion was sufficient during both protocols to reach an adequate plasma dobutamine concentration, which induced a detectable increase of wall thickening in all patients. There is a significant differences between the two protocols with regard to the plasma catecholamine changes, so some of the hemodynamic effects during the stepwise dobutamineinfusion protocol may be mediated through release of endogenous catecholamines.
The aim of the study was to compare the extent and severity of reversible underperfusion in silen... more The aim of the study was to compare the extent and severity of reversible underperfusion in silent versus painful myocardial ischaemia during the dobutamine stress test. A consecutive series of 85 patients with significant coronary artery disease and reversible perfusion defects on technetium-99m methoxyisobutylisonitrile single-photon emission tomography performed at rest and during high-dose dobutamine stress (up to 40 gg kg q min 1) were studied. The left ventricle was divided into six segments. An ischaemic perfusion score was derived quantitatively by subtracting the rest from the stress defect score. Patients with multivessel disease had a higher ischaemic score (610_762 vs 310_411, P<0.05) and a higher number of reversible perfusion defects (2.1_+1.2 vs 1.1_+0.8, P<0.01) than patients with singlevessel disease. Typical angina occurred in 37 patients (44%) during the test. There was no significant difference between patients with and patients without angina with respect to age, gender, peak rate-pressure product, prevalence of previous myocardial infarction, diabetes mellitus, multivessel disease or number of stenotic coronary arteries. Stress, rest and ischaemic scores as well as the number and distribution of reversible defects were not different in patients with and patients without angina. Patients with angina more frequently had a history of typical angina before the test (43% vs 17%, P<0.01) and ST-segment depression during the test (54% vs 25%, P<0.01). It is concluded that in patients with coronary artery disease and ischaemia detected by dobutamine scintigraphy, the extent and severity of coronary artery disease and myocardial perfusion abnormalities are similar with or without angina during stress testing.
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Papers by Jan Cornel