Publications by authors named "Mark Y Chan"

113 Publications

Differential modulation of polyunsaturated fatty acids in patients with myocardial infarction treated with ticagrelor or clopidogrel.

Cell Rep Med 2021 Jun 4;2(6):100299. Epub 2021 Jun 4.

Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.

Untargeted metabolomics is used to refine the development of biomarkers for the diagnosis of cardiovascular disease. Myocardial infarction (MI) has major individual and societal consequences for patients, who remain at high risk of secondary events, despite advances in pharmacological therapy. To monitor their differential response to treatment, we performed untargeted plasma metabolomics on 175 patients from the platelet inhibition and patient outcomes (PLATO) trial treated with ticagrelor and clopidogrel, two common PY inhibitors. We identified a signature that discriminates patients, which involves polyunsaturated fatty acids (PUFAs) and particularly the omega-3 fatty acids docosahexaenoate and eicosapentaenoate. The known cardiovascular benefits of PUFAs could contribute to the efficacy of ticagrelor. Our work, beyond pointing out the high relevance of untargeted metabolomics in evaluating response to treatment, establishes PUFA metabolism as a pathway of clinical interest in the recovery path from MI.
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http://dx.doi.org/10.1016/j.xcrm.2021.100299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233657PMC
June 2021

Outcomes of a multi-ethnic Asian population on combined treatment with clopidogrel and omeprazole in 12,440 patients.

J Thromb Thrombolysis 2021 May 6. Epub 2021 May 6.

National University Heart Centre, National University of Singapore, Singapore, Singapore.

Omeprazole is commonly co-prescribed with clopidogrel. Clopidogrel requires bio-activation by cytochrome P450 CYP2C19. Omeprazole may reduce clopidogrel's antithrombotic efficacy by inhibiting CYP2C19. Studies in Caucasians receiving omeprazole with clopidogrel showed no significant increase in death and myocardial infarction with this drug-drug interaction. There are limited large-scale studies in Asians, who may have a greater prevalence of CYP2C19 loss-of-function polymorphisms. A single centre retrospective cohort study was undertaken based on a review of medication records and prescription data. Patients prescribed clopidogrel from 2009 to 2012 were followed-up with until December 2012 (median:29 months). The primary outcome was all-cause mortality and secondary outcomes were myocardial infarction (MI), cerebrovascular accidents, and subsequent coronary interventions. Of 12,440 patients prescribed clopidogrel, 62%(n = 7714) were on omeprazole (63.8% Chinese, 13.9% Malay, 12.4% Indian, 10.0% others), and 38%(n = 4726) were not on omeprazole or other proton pump inhibitors (62.6% Chinese, 13.5% Malay, 10.7% Indian, 13.2% others). Mortality after co-prescription occurred in 14.3%(n = 1101) of patients, compared to 6.3%(n = 300) of patients prescribed clopidogrel only. Multivariate analysis using propensity score adjusted analysis showed no significant increase in all-cause mortality with co-prescription (adjusted hazards ratio [AHR] 1.13, [95%CI 0.95-1.35]). Patients on co-prescription had a higher risk of subsequent MI (16% vs 3.8%; AHR 2.03 [95%CI 1.70-2.44]), but not of cerebrovascular accidents (5.0% vs 2.0%; AHR 0.98 [95%CI 0.76-1.27]) or coronary interventions (1.7% vs 0.7%; AHR 1.28 [95%CI 0.83-1.96]). The risk of a subsequent MI was higher in the Malay (AHR 2.43 [95%CI 1.68-3.52]) and Chinese (AHR 2.06 [95%CI 1.63-2.60]) population as compared to the Indian (AHR 1.56 [95%CI 1.06-2.31]) population. In conclusion, the use of clopidogrel with omeprazole is associated with an increased risk of MI, but not mortality or stroke, in this multi-ethnic Asian population. These risks appear to vary among different ethnic groups.
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http://dx.doi.org/10.1007/s11239-021-02472-wDOI Listing
May 2021

A deep learning pipeline for automatic analysis of multi-scan cardiovascular magnetic resonance.

J Cardiovasc Magn Reson 2021 04 26;23(1):47. Epub 2021 Apr 26.

Centre for Translational MR Research (TMR), National University of Singapore, Singapore, 117549, Singapore.

Background: Cardiovascular magnetic resonance (CMR) sequences are commonly used to obtain a complete description of the function and structure of the heart, provided that accurate measurements are extracted from images. New methods of extraction of information are being developed, among them, deep neural networks are powerful tools that showed the ability to perform fast and accurate segmentation. Iq1n order to reduce the time spent by reading physicians to process data and minimize intra- and inter-observer variability, we propose a fully automatic multi-scan CMR image analysis pipeline.

Methods: Sequence specific U-Net 2D models were trained to perform the segmentation of the left ventricle (LV), right ventricle (RV) and aorta in cine short-axis, late gadolinium enhancement (LGE), native T1 map, post-contrast T1, native T2 map and aortic flow sequences depending on the need. The models were trained and tested on a set of data manually segmented by experts using semi-automatic and manual tools. A set of parameters were computed from the resulting segmentations such as the left ventricular and right ventricular ejection fraction (EF), LGE scar percentage, the mean T1, T1 post, T2 values within the myocardium, and aortic flow. The Dice similarity coefficient, Hausdorff distance, mean surface distance, and Pearson correlation coefficient R were used to assess and compare the results of the U-Net based pipeline with intra-observer variability. Additionally, the pipeline was validated on two clinical studies.

Results: The sequence specific U-Net 2D models trained achieved fast (≤ 0.2 s/image on GPU) and precise segmentation over all the targeted region of interest with high Dice scores (= 0.91 for LV, = 0.92 for RV, = 0.93 for Aorta in average) comparable to intra-observer Dice scores (= 0.86 for LV, = 0.87 for RV, = 0.95 for aorta flow in average). The automatically and manually computed parameters were highly correlated (R = 0.91 in average) showing results superior to the intra-observer variability (R = 0.85 in average) for every sequence presented here.

Conclusion: The proposed pipeline allows for fast and robust analysis of large CMR studies while guaranteeing reproducibility, hence potentially improving patient's diagnosis as well as clinical studies outcome.
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http://dx.doi.org/10.1186/s12968-020-00695-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074440PMC
April 2021

Long-term clinical outcomes of biodegradable polymer drug eluting stents versus second-generation durable polymer drug eluting stents for ST-segment elevation myocardial infarction.

Cardiovasc Revasc Med 2021 Apr 16. Epub 2021 Apr 16.

National University Heart Center, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Background: Biodegradable polymer drug eluting stents (BP-DES) may offer the advantage of vascular healing in ST-segment elevation myocardial infarction (STEMI). Long-term outcome data comparing BP-DES and second-generation durable polymer drug eluting stents (DP-DES) in STEMI is lacking. This study aims to compare the long-term clinical outcomes of BP-DES versus second-generation DP-DES in STEMI.

Methods: This is an observational study of consecutive patients with STEMI who received either BP-DES (n = 854) or DP-DES (n = 708) during primary percutaneous coronary intervention (PCI) from 1st February 2007 to 31st December 2016. The primary outcome was target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (MI), and target lesion revascularization with follow up till 30th November 2019.

Results: The baseline demographics, lesion and procedural characteristic were similar between the two groups except for more prior MI and chronic obstructive pulmonary disease in the BP-DES group. At a median follow up of 4.2 years (interquartile range: 2.6-6.2 years), the incidence of TLF was similar between BP-DES and DP-DES (adjusted hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.70-1.26). Likewise, incidence of major adverse cardiovascular events (MACE: all-cause death, any MI or target vessel revascularization) and definite stent thrombosis were similar in both groups (MACE: adjusted HR 1.04, 95% CI 0.82-1.32; definite stent thrombosis: adjusted HR 1.06, 95% CI 0.31-3.64).

Conclusion: Among patients with STEMI who underwent primary PCI, BP-DES and DP-DES implantation was associated with similar long-term clinical outcomes.
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http://dx.doi.org/10.1016/j.carrev.2021.04.014DOI Listing
April 2021

Association of Global Cardiac Calcification with Atrial Fibrillation and Recurrent Stroke in Patients with Embolic Stroke of Undetermined Source.

J Am Soc Echocardiogr 2021 Apr 16. Epub 2021 Apr 16.

Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Cardiology, National University Heart Centre Singapore, Singapore.

Background: Calcium deposits in the heart have been associated with cardiovascular events, mortality, stroke, and atrial fibrillation (AF). However, there is no accepted standard method for scoring cardiac calcifications. Existing methods have also not been validated for the assessment of patients with embolic stroke of undetermined source (ESUS). The aim of this study was to evaluate the association of various cardiac calcification scores with new-onset AF and stroke recurrence in a cohort of patients with ESUS.

Methods: In this study, 181 consecutive patients with stroke diagnosed with ESUS were identified and evaluated. They were followed for new-onset AF and ischemic stroke recurrence for a median duration of 2.1 years. Various echocardiographic cardiac calcification scores were assessed on transthoracic echocardiography performed during the evaluation of ESUS and subsequently assessed for their relation to AF detection and recurrent stroke. The echocardiographic calcium scores assessed were the (1) global cardiac calcium score (GCCS), (2) echocardiographic calcium score (eCS), (3) echocardiographic calcification score, (4) echocardiographic composite cardiac calcium score, and (5) total heart calcification score. Only two of these scoring schemes, GCCS and eCS, quantified the cardiac calcium burden.

Results: Higher calcium scores as measured by GCCS and eCS were found to be significantly associated with subsequent AF detection as well as recurrent ischemic stroke in patients with ESUS. The association with recurrent stroke remained significant even after adjustment for comorbidities and AF.

Conclusions: Higher cardiac calcification measured using the GCCS and eCS is independently associated with AF detection and recurrent ischemic stroke in patients with ESUS, and these scores can be useful markers for further risk stratification in patients with ESUS.
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http://dx.doi.org/10.1016/j.echo.2021.04.008DOI Listing
April 2021

Obesity in COVID-19: A Systematic Review and Meta-analysis.

Ann Acad Med Singap 2020 12;49(12):996-1008

Department of Cardiology, National University Heart Centre, Singapore.

Objective: Obesity has been shown to be associated with adverse outcomes in viral infections such as influenza, but previous studies on coronavirus disease 2019 (COVID-19) had mixed results. The aim of this systematic review is to investigate the relationship between COVID-19 and obesity.

Methods: We performed a systematic review and meta-analysis. A literature search of MEDLINE, EMBASE, Scopus, Web of Science, CENTRAL, OpenGrey and preprint servers medRxiv and bioRxiv was performed, with no restriction on language or date of publication. Primary outcomes of this study were intensive care unit (ICU) admission or critical disease, severe disease and mortality. Secondary outcome was a positive COVID-19 test. Meta-analysis was performed using OpenMeta-Analyst software, and heterogeneity was tested using Cochran's Q test and I2 statistic. The study protocol was registered on PROSPERO (CRD42020184953).

Results: A total of 1,493 articles were identified and 61 studies on 270,241 patients were included. The pooled prevalence of obesity was 27.6% (95% confidence interval [CI] 22.0-33.2) in hospitalised patients. Obesity was not significantly associated with increased ICU admission or critical illness (odds ratio [OR] 1.25, 95% CI 0.99-1.58, =0.062, I =31.0) but was significantly associated with more severe disease (OR 3.13, 95% CI 1.41-6.92, =0.005, I =82.6), mortality (OR 1.36, 95% CI 1.09-1.69, =0.006, I=88.5) and a positive COVID-19 test (OR 1.50, 95% CI 1.25-1.81, <0.001).

Conclusion: Obesity increased the risk of severe disease, mortality and infection with COVID-19. Higher body mass index was associated with ICU admission and critical disease. Patients who are obese may be more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and infected patients should be monitored closely for adverse outcomes.
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December 2020

Low miR-19b-1-5p Expression Is Related to Aspirin Resistance and Major Adverse Cardio- Cerebrovascular Events in Patients With Acute Coronary Syndrome.

J Am Heart Assoc 2021 01 14;10(2):e017120. Epub 2021 Jan 14.

Departments of Clinical Epidemiology, Biostatistics and Bio-informaticsAmsterdam UMC, location AMC Amsterdam The Netherlands.

Background Because of a nonresponse to aspirin (aspirin resistance), patients with acute coronary syndrome (ACS) are at increased risk of developing recurrent event. The in vitro platelet function tests have potential limitations, making them unsuitable for the detection of aspirin resistance. We investigated whether miR-19b-1-5p could be utilized as a biomarker for aspirin resistance and future major adverse cardio-cerebrovascular (MACCE) events in patients with ACS. Methods and Results In this cohort study, patients with ACS were enrolled from multiple tertiary hospitals in Christchurch, Hong Kong, Sarawak, and Singapore between 2011 and 2015. MiR-19b-1-5p expression was measured from buffy coat of patients with ACS (n=945) by reverse transcription quantitative polymerase chain reaction. Platelet function was determined by Multiplate aggregometry testing. MACCE was collected over a mean follow-up time of 1.01±0.43 years. Low miR-19b-1-5p expression was found to be related to aspirin resistance as could be observed from sustained platelet aggregation in the presence of aspirin (-Log-miR-19b-1-5p, [unstandardized beta, 44.50; 95% CI, 2.20-86.80; <0.05]), even after adjusting for age, sex, ethnicity, and prior history of stroke. Lower miR-19b-1-5p expression was independently associated with a higher risk of MACCE (-Log-miR-19b-1-5p, [hazard ratio, 1.85; 95% CI, 1.23-2.80; <0.05]). Furthermore, a significant interaction was noted between the inverse miR-19b-1-5p expression and family history of premature coronary artery disease (=0.01) on the risk of MACCE. Conclusions Lower miR-19b-1-5p expression was found to be associated with sustained platelet aggregation on aspirin, and a higher risk of MACCE in patients with ACS. Therefore, miR-19b-1-5p could be a suitable marker for aspirin resistance and might predict recurrence of MACCE in patients with ACS.
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http://dx.doi.org/10.1161/JAHA.120.017120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955314PMC
January 2021

Remote Postdischarge Treatment of Patients With Acute Myocardial Infarction by Allied Health Care Practitioners vs Standard Care: The IMMACULATE Randomized Clinical Trial.

JAMA Cardiol 2021 Jul;6(7):830-835

Cardiovascular Research Institute, Yong Loo-Lin School of Medicine, National University of Singapore, Singapore.

Importance: There are few data on remote postdischarge treatment of patients with acute myocardial infarction.

Objective: To compare the safety and efficacy of allied health care practitioner-led remote intensive management (RIM) with cardiologist-led standard care (SC).

Design, Setting, And Participants: This intention-to-treat feasibility trial randomized patients with acute myocardial infarction undergoing early revascularization and with N-terminal-pro-B-type natriuretic peptide concentration more than 300 pg/mL to RIM or SC across 3 hospitals in Singapore from July 8, 2015, to March 29, 2019. RIM participants underwent 6 months of remote consultations that included β-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACE-I/ARB) dose adjustment by a centralized nurse practitioner team while SC participants were treated face-to-face by their cardiologists.

Main Outcomes And Measures: The primary safety end point was a composite of hypotension, bradycardia, hyperkalemia, or acute kidney injury requiring hospitalization. To assess the efficacy of RIM in dose adjustment of β-blockers and ACE-I/ARBs compared with SC, dose intensity scores were derived by converting comparable doses of different β-blockers and ACE-I/ARBs to a scale from 0 to 5. The primary efficacy end point was the 6-month indexed left ventricular end-systolic volume (LVESV) adjusted for baseline LVESV.

Results: Of 301 participants, 149 (49.5%) were randomized to RIM and 152 (50.5%) to SC. RIM and SC participants had similar mean (SD) age (55.3 [8.5] vs 54.7 [9.1] years), median (interquartile range) N-terminal-pro-B-type natriuretic peptide concentration (807 [524-1360] vs 819 [485-1320] pg/mL), mean (SD) baseline left ventricular ejection fraction (57.4% [11.1%] vs 58.1% [10.3%]), and mean (SD) indexed LVESV (32.4 [14.1] vs 30.6 [11.7] mL/m2); 15 patients [5.9%] had a left ventricular ejection fraction <40%. The primary safety end point occurred in 0 RIM vs 2 SC participants (1.4%) (P = .50). The mean β-blocker and ACE-I/ARB dose intensity score at 6 months was 3.03 vs 2.91 (adjusted mean difference, 0.12 [95% CI, -0.02 to 0.26; P = .10]) and 2.96 vs 2.77 (adjusted mean difference, 0.19 [95% CI, -0.02 to 0.40; P = .07]), respectively. The 6-month indexed LVESV was 28.9 vs 29.7 mL/m2 (adjusted mean difference, -0.80 mL/m2 [95% CI, -3.20 to 1.60; P = .51]).

Conclusions And Relevance: Among low-risk patients with revascularization after myocardial infarction, RIM by allied health care professionals was feasible and safe. There were no differences in achieved medication doses or indices of left ventricular remodeling. Further studies of RIM in higher-risk cohorts are warranted.

Trial Registration: ClinicalTrials.gov Identifier: NCT02468349.
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http://dx.doi.org/10.1001/jamacardio.2020.6721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774042PMC
July 2021

Impact of COVID-19 on health-related quality of life in patients with cardiovascular disease: a multi-ethnic Asian study.

Health Qual Life Outcomes 2020 Dec 14;18(1):387. Epub 2020 Dec 14.

Biostatistics, Singapore Clinical Research Institute, Singapore, Singapore.

Background: Little is known about the impact of the global coronavirus disease-2019 (COVID-19) pandemic on patients with cardiovascular disease (CVD), the biggest global killer and major risk factor for severe COVID-19 infections. We aim to explore the indirect consequences of COVID-19 on health-related quality of life (HRQoL) of patients with CVD.

Methods: Eighty-one adult outpatients with CVD were assessed using the EQ-5D, a generic health status instrument with five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), before and during the pandemic. Changes in the EQ-5D dimensional responses were compared categorically as well as using the dimension-specific sum-score (range 1-3, with a higher score indicating worse health). The responses and sum-score were compared using the exact test of symmetry and the paired t-test, respectively.

Results: These patients [mean age (SD) 59.8 (10.5); 92.6% males; 56% New York Heart Association (NYHA) functional class I] had coronary artery disease (69%), heart failure (28%), or arrhythmias (15%). None experienced change in NYHA class between assessments. About 30% and 38% of patients reported problems with at least one of the EQ-5D dimensions pre-pandemic and during the pandemic, respectively. The highest increase in health problems was reported for anxiety/depression (12.5% pre-pandemic vs 23.5% during pandemic; p = 0.035) with mean domain-specific score from 1.12 (SD 0.33) to 1.25 (SD 0.46) (standardized effect size = 0.373, p = 0.012). There was no meaningful change in other dimensions as well as overall HRQoL.

Conclusion: The COVID-19 pandemic is associated with a significant worsening of the mental health of patients with CVD.
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http://dx.doi.org/10.1186/s12955-020-01640-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734458PMC
December 2020

Association of Electrocardiographic P-Wave Markers and Atrial Fibrillation in Embolic Stroke of Undetermined Source.

Cerebrovasc Dis 2021 11;50(1):46-53. Epub 2020 Dec 11.

Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Background: Several P-wave indices are thought to represent underlying atrial remodeling and have been associated with ischaemic stroke even in the absence of atrial fibrillation (AF). However, the utility of these P-wave indices in predicting outcomes in patients with embolic stroke of undetermined source (ESUS) has not been studied. The aim of this study is to examine these different P-wave indices towards predicting new-onset AF and stroke recurrence in a cohort of patients with ESUS, thereby demonstrating the value of these electrocardiographic markers for stroke risk stratification.

Methods: Between October 2014 and October 2017, consecutive patients diagnosed with ESUS were followed for new-onset AF and ischaemic stroke recurrence. The various P-wave indices, namely, the P-terminal force in the precordial lead V1 (PTFV1), P-wave duration, P-wave dispersion, interatrial blocks, and P-wave axis, were assessed on the initial electrocardiogram on presentation and studied for their relation to eventual AF detection and recurrent stroke.

Results: 181 ischaemic stroke patients with ESUS were recruited and followed up for a median duration of 2.1 years. An abnormal PTFV1 was associated with occult AF detection but not with recurrent ischaemic strokes. No significant association was observed between the other P-wave indices with either occult AF or stroke recurrence.

Conclusion: PTFV1 is associated with AF detection but not recurrent strokes in ESUS patients and can be a useful electrocardiographic marker for further risk stratification in ESUS patients.
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http://dx.doi.org/10.1159/000512179DOI Listing
August 2021

A 78-year-old male with inferior ST-segment elevation on electrocardiogram, diabetic ketoacidosis and acute pancreatitis.

Cardiovasc Endocrinol Metab 2020 Dec 17;9(4):186-188. Epub 2020 Apr 17.

Department of Cardiology, National University Heart Centre Singapore, National University Health System.

A 78-year-old male presented with shortness of breath, metabolic acidosis, severe hyperglycaemia and ketonemia. Inferior ST-elevation was present on 12-lead ECG with raised troponin I, but coronary arteries were normal on emergency cardiac catheterization. Despite no previous history of diabetes mellitus and normal HbA1c levels 7 months prior, diabetic ketoacidosis (DKA) was diagnosed, complicated by subsequent shock. The underlying cause was acute pancreatic disease, supported by elevated pancreatic enzyme levels and a history of chronic heavy alcohol use. There are no previous reports, to our knowledge, of patients with acute pancreatitis presenting to the ED with secondary DKA mimicking STEMI.
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http://dx.doi.org/10.1097/XCE.0000000000000205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673775PMC
December 2020

Effect of Ticagrelor on Left Ventricular Remodeling in Patients With ST-Segment Elevation Myocardial Infarction (HEALING-AMI).

JACC Cardiovasc Interv 2020 10;13(19):2220-2234

Department of Internal Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, South Korea. Electronic address:

Objectives: The aim of this study was to evaluate the effect of ticagrelor versus clopidogrel on left ventricular (LV) remodeling after reperfusion of ST-segment elevation myocardial infarction (STEMI) in humans.

Background: Animal studies have demonstrated that ticagrelor compared with clopidogrel better protects myocardium against reperfusion injury and improves remodeling after myocardial infarction.

Methods: In this investigator-initiated, randomized, open-label, assessor-blinded trial performed at 10 centers in Korea, patients were enrolled if they had naive STEMI successfully treated with primary percutaneous coronary intervention (PCI) and at least 6-month planned duration of dual-antiplatelet treatment. The coprimary endpoints were LV remodeling index (LVRI) (a relative change of LV end-diastolic volume) measured on 3-dimensional echocardiography and N-terminal pro-B-type natriuretic peptide level at 6 months.

Results: Among initially enrolled patients with STEMI (n = 336), 139 in each group completed the study. LVRI at 6 months was numerically lower with ticagrelor versus clopidogrel (0.6 ± 18.6% vs. 4.5 ± 16.5%; p = 0.095). Ticagrelor significantly reduced the 6-month level of N-terminal pro-B-type natriuretic peptide (173 ± 141 pg/ml vs. 289 ± 585 pg/ml; p = 0.028). These differences were prominent in patients with pre-PCI TIMI (Thrombolysis In Myocardial Infarction) flow grade 0. By multivariate analysis, ticagrelor versus clopidogrel reduced the risk for positive LV remodeling (LVRI >0%) (odds ratio: 0.56; 95% confidence interval: 0.33 to 0.95; p = 0.030). The LV end-diastolic volume index remained unchanged during ticagrelor treatment (from 54.7 ± 12.2 to 54.2 ± 12.2 ml/m; p = 0.629), but this value increased over time during clopidogrel treatment (from 54.6 ± 11.3 to 56.4 ± 13.9 ml/m; p = 0.056) (difference -2.3 ml/m; 95% confidence interval: -4.8 to 0.2 ml/m; p = 0.073). Ticagrelor reduced LV end-systolic volume index (from 27.0 ± 8.5 to 24.7 ± 8.4 ml/m; p < 0.001), whereas no reduction was seen with clopidogrel (from 26.2 ± 8.9 to 25.6 ± 11.0 ml/m; p = 0.366) (difference -1.8 ml/m; 95% confidence interval: -3.5 to -0.1 ml/m; p = 0.040).

Conclusions: Ticagrelor was superior to clopidogrel for LV remodeling after reperfusion of STEMI with primary PCI. (High Platelet Inhibition With Ticagrelor to Improve Left Ventricular Remodeling in Patients With ST Segment Elevation Myocardial Infarction [HEALING-AMI]; NCT02224534).
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http://dx.doi.org/10.1016/j.jcin.2020.08.007DOI Listing
October 2020

Beta-blockers and renin-angiotensin system inhibitors in acute myocardial infarction managed with inhospital coronary revascularization.

Sci Rep 2020 09 16;10(1):15184. Epub 2020 Sep 16.

Department of Cardiology, National University Heart Centre Singapore, 1E Kent Ridge Road, NUHS Tower Block, Level 9, Singapore, 119228, Singapore.

Pivotal trials of beta-blockers (BB) and angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) in acute myocardial infarction (AMI) were largely conducted prior to the widespread adoption of early revascularization. A total of 15,073 patients with AMI who underwent inhospital coronary revascularization from January 2007 to December 2013 were analyzed. At 12 months, BB was significantly associated with a lower incidence of major adverse cardiovascular events (MACE, adjusted HR 0.80, 95% CI 0.70-0.93) and all-cause mortality (adjusted HR 0.69, 95% CI 0.55-0.88), while ACEI/ARB was significantly associated with lower all-cause mortality (adjusted HR 0.80, 95% CI 0.66-0.98) and heart failure (HF) hospitalization (adjusted HR 0.80, 95% CI 0.68-0.95). Combined BB and ACEI/ARB use was associated with the lowest incidence of MACE (adjusted HR 0.70, 95% CI 0.57-0.86), all-cause mortality (adjusted HR 0.55, 95% CI 0.40-0.77) and HF hospitalization (adjusted HR 0.64, 95% CI 0.48-0.86). This were consistent for left ventricular ejection fraction < 50% or ≥ 50%. In conclusion, in AMI managed with revascularization, both BB and ACEI/ARB were associated with a lower incidence of 12-month all-cause mortality. Combined BB and ACEI/ARB was associated with the lowest incidence of all-cause mortality and HF hospitalization.
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http://dx.doi.org/10.1038/s41598-020-72232-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495427PMC
September 2020

Prioritizing Candidates of Post-Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics.

Circulation 2020 10 4;142(15):1408-1421. Epub 2020 Sep 4.

Department of Medicine, Yong Loo-Lin School of Medicine, National University of Singapore (M.Y.C., M.E., S.H.T., C.L.D., L.H.L., W.-M.S., J.P.L., C.-H.L., R.S.Y.F., M.A.A.-J., A.M.R.).

Background: Heart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene expression may identify new candidates for biomarker and drug target discovery.

Methods: We used aptamer-based affinity-capture plasma proteomics to measure 1305 plasma proteins at 1 month post-MI in a New Zealand cohort (CDCS [Coronary Disease Cohort Study]) including 181 patients post-MI who were subsequently hospitalized for HF in comparison with 250 patients post-MI who remained event free over a median follow-up of 4.9 years. We then correlated plasma proteins with left ventricular ejection fraction measured at 4 months post-MI and identified proteins potentially coregulated in post-MI HF using weighted gene co-expression network analysis. A Singapore cohort (IMMACULATE [Improving Outcomes in Myocardial Infarction through Reversal of Cardiac Remodelling]) of 223 patients post-MI, of which 33 patients were hospitalized for HF (median follow-up, 2.0 years), was used for further candidate enrichment of plasma proteins by using Fisher meta-analysis, resampling-based statistical testing, and machine learning. We then cross-referenced differentially expressed proteins with their differentially expressed genes from single-cell transcriptomes of nonmyocyte cardiac cells isolated from a murine MI model, and single-cell and single-nucleus transcriptomes of cardiac myocytes from murine HF models and human patients with HF.

Results: In the CDCS cohort, 212 differentially expressed plasma proteins were significantly associated with subsequent HF events. Of these, 96 correlated with left ventricular ejection fraction measured at 4 months post-MI. Weighted gene co-expression network analysis prioritized 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF in comparison with event-free controls (data set 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (data set 2), whereas single-cell transcriptomes identified 15 gene-protein candidates (data set 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly enriched proteins that were common to all 3 data sets included well-established biomarkers of post-MI HF: N-terminal B-type natriuretic peptide and troponin T, and newly emergent biomarkers, angiopoietin-2, thrombospondin-2, latent transforming growth factor-β binding protein-4, and follistatin-related protein-3, as well.

Conclusions: Large-scale human plasma proteomics, cross-referenced to unbiased cardiac transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547904PMC
October 2020

Cardiac and renal biomarkers in recreational runners following a 21 km treadmill run.

Clin Cardiol 2020 Dec 3;43(12):1443-1449. Epub 2020 Sep 3.

Cardiac Department, National University Heart Centre Singapore, Singapore, Singapore.

Background: Highly trained athletes running 42 km or more demonstrate elevated cardiac biomarkers, ventricular dysfunction, and decreased glomerular filtration rate (GFR). Whether similar changes occur in the much larger population of recreational runners following half-marathon distance running is unclear.

Hypothesis: Recreational runners exhibit changes in myocardial and renal biomarkers, including ventricular strain, after a half-marathon treadmill run.

Methods: 10 recreational subjects (mean age 36.5 ± 6.5 years) ran 21 km on a treadmill (mean completion time 121.6 ± 16.1 minutes). Serum high-sensitivity troponin T (hsTnT), amino-terminal pro-brain natriuretic peptide (NT-proBNP), creatinine, and neutrophil gelatinase-associated lipocalin (NGAL) were measured prior to, 1 hour post-, and 24 hours post-exercise. Pre- and post-exercise echocardiograms were performed.

Results: All biomarkers increased 1 hour post-exercise: hsTnT by 8.5 ± 8.5 pg/ml (P < .05), NT-ProBNP by 26.2 ± 22.8 pg/ml (P < .05) and NGAL by 29.5 ± 37.7 ng/ml (P=NS). By 24 hours post-run, these biomarkers declined toward baseline levels. Right ventricle (RV) free wall and left ventricle global longitudinal strain decreased by 5.5% and 1.8%, respectively (P < .001). Changes in NGAL correlated well with changes in serum creatinine (R = 0.79, P < .01) and GFR (R = -0.73, P < .05). Faster 21 km completion times, and a larger reduction in post-exercise RV strain, were associated with higher NGAL levels: (R = -0.75, P = .01) and (R = 0.66, P < .05), respectively.

Conclusion: A 21 km run in recreational runners is associated with transient ventricular stunning and reversible changes in myocardial and renal biomarkers. Whether repeated bouts of similar activity contributes to chronic cardiac or kidney dysfunction deserves further evaluation.
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http://dx.doi.org/10.1002/clc.23459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724216PMC
December 2020

Left Atrial Volume Index Predicts New-Onset Atrial Fibrillation and Stroke Recurrence in Patients with Embolic Stroke of Undetermined Source.

Cerebrovasc Dis 2020 17;49(3):285-291. Epub 2020 Jun 17.

Division of Neurology, Department of Medicine, National University Health System, Singapore, Singapore.

Introduction: It is unclear which surrogate of atrial cardiopathy best predicts the risk of developing a recurrent ischemic stroke in embolic stroke of undetermined source (ESUS). Left atrial diameter (LAD) and LAD index (LADi) are often used as markers of left atrial enlargement in current ESUS research, but left atrial volume index (LAVi) has been found to be a better predictor of cardiovascular outcomes in other patient populations.

Objective: We aim to compare the performance of LAVi, LAD, and LADi in predicting the development of new-onset atrial fibrillation (AF) and stroke recurrence in ESUS.

Methods: Between October 2014 and October 2017, consecutive patients diagnosed with ESUS were followed for new-onset AF, ischemic stroke recurrence, and a composite outcome of occult AF and stroke recurrence. LAVi and LADi were measured by transthoracic echocardiogram; "high" LAVi was defined as ≥35 mL/m2 in accordance with American Society of Echocardiography guidelines.

Results: 185 ischemic stroke patients with ESUS were recruited and followed for a median duration of 2.1 years. Increased LAVi was associated with new-onset AF detection (aOR 1.08; 95% CI 1.03-1.14; p = 0.003) and stroke recurrence (aOR 1.05; 95% CI 1.01-1.10; p = 0.026). Patients with "high" LAVi had a higher likelihood of developing a composite of AF detection and stroke recurrence (HR 3.45; 95% CI 1.55-7.67; p = 0.002). No significant association was observed between LADi and either occult AF or stroke recurrence.

Conclusions: LAVi is associated with new-onset AF and stroke recurrence in ESUS patients and may be a better surrogate of atrial cardiopathy.
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http://dx.doi.org/10.1159/000508211DOI Listing
November 2020

LipidCreator workbench to probe the lipidomic landscape.

Nat Commun 2020 04 28;11(1):2057. Epub 2020 Apr 28.

Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., 44139, Dortmund, Germany.

Mass spectrometry (MS)-based targeted lipidomics enables the robust quantification of selected lipids under various biological conditions but comprehensive software tools to support such analyses are lacking. Here we present LipidCreator, a software that fully supports targeted lipidomics assay development. LipidCreator offers a comprehensive framework to compute MS/MS fragment masses for over 60 lipid classes. LipidCreator provides all functionalities needed to define fragments, manage stable isotope labeling, optimize collision energy and generate in silico spectral libraries. We validate LipidCreator assays computationally and analytically and prove that it is capable to generate large targeted experiments to analyze blood and to dissect lipid-signaling pathways such as in human platelets.
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http://dx.doi.org/10.1038/s41467-020-15960-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188904PMC
April 2020

Circulating MicroRNA Profiling in Non-ST Elevated Coronary Artery Syndrome Highlights Genomic Associations with Serial Platelet Reactivity Measurements.

Sci Rep 2020 04 10;10(1):6169. Epub 2020 Apr 10.

National University of Singapore, Singapore, Singapore.

Changes in platelet physiology are associated with simultaneous changes in microRNA concentrations, suggesting a role for microRNA in platelet regulation. Here we investigated potential associations between microRNA and platelet reactivity (PR), a marker of platelet function, in two cohorts following a non-ST elevation acute coronary syndrome (NSTE-ACS) event. First, non-targeted microRNA concentrations and PR were compared in a case (N = 77) control (N = 76) cohort within the larger TRILOGY-ACS trial. MicroRNA significant in this analysis plus CVD-associated microRNAs from the literature were then quantified by targeted rt-PCR in the complete TRILOGY-ACS cohort (N = 878) and compared with matched PR samples. Finally, microRNA significant in the non-targeted & targeted analyses were verified in an independent post NSTE-ACS cohort (N = 96). From the non-targeted analysis, 14 microRNAs were associated with PR (Fold Change: 0.91-1.27, p-value: 0.004-0.05). From the targeted analysis, five microRNAs were associated with PR (Beta: -0.09-0.22, p-value: 0.004-0.05). Of the 19 significant microRNAs, three, miR-15b-5p, miR-93 and miR-126, were consistently associated with PR in the TRILOGY-ACS and independent Singapore post-ACS cohorts, suggesting the measurement of circulating microRNA concentrations may report on dynamic changes in platelet biology following a cardiovascular ischemic event.
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http://dx.doi.org/10.1038/s41598-020-63263-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148370PMC
April 2020

E/e' in relation to outcomes in ST-elevation myocardial infarction.

Echocardiography 2020 04 3;37(4):554-560. Epub 2020 Apr 3.

National Heart Centre Singapore, Singapore City, Singapore.

Background: Myocardial infarction (MI) is a high-risk condition especially when filling pressure is raised, and earlier reports have suggested that E/e' is associated with poor outcome. However, whether E/e' predicts risk better than LVEF, which is the current standard of practice, is not known. We investigated this question in the largest and most rigorous study of MI patients so far.

Methods And Results: We studied 660 patients with ST-elevation MI (STEMI) treated with primary percutaneous coronary intervention and related E/e' to short-term mortality (in-hospital death), as well as long-term events at 2 years comprising (a) a composite of MI, stroke, heart failure, and death, and (b) death alone. Short-term models were adjusted for age, sex, and LVEF. Long-term models were adjusted for age, sex, diabetes, revascularization procedure, history of MI, hypertension, renal function, drugs on discharge, and LVEF. Elevated E/e'> 15 indicated higher risk of short-term events (n = 19:7.0% (95% confidence interval 3.4-10.8%) vs. 1.0% (0.3 - 2.3%); adjusted odds ratio 3.7 (1.3-10.5)). While elevated E/e' was also associated with long-term outcomes (n = 103 composite events: 15.9% (11.9% - 21.4%) vs 6.8% (5.2% - 8.7%), P < .001; n = 38 death events: 6.0% (3.9% - 9.5%) vs 2.0% (1.3% - 3.2%), P = .001), E/e' was rendered nonsignificant for long-term outcomes by multivariable adjustment (p = ns for both). LVEF, on the contrary, was a highly significant predictor in the adjusted long-term model.

Conclusion: E/e' is associated with poor outcome in STEMI, but LVEF is a stronger predictor of long-term risk.
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http://dx.doi.org/10.1111/echo.14652DOI Listing
April 2020

Treating Very Long Coronary Artery Lesions in the Contemporary Drug-Eluting-Stent Era: Single Long 48 mm Stent Versus Two Overlapping Stents Showed Comparable Clinical Outcomes.

Cardiovasc Revasc Med 2020 09 13;21(9):1115-1118. Epub 2020 Feb 13.

Department of Cardiology, National University Heart Center, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Background/purpose: Percutaneous coronary intervention (PCI) of diffuse coronary artery disease (CAD) is associated with higher adverse clinical events. This study aimed to compare the clinical outcomes of patients treated with single long 48 mm contemporary drug eluting stents (SL-DES) versus two overlapping contemporary drug eluting stents (OL-DES) for very-long CAD.

Methods/materials: We analyzed the clinical outcome of 117 patients with SL-DES and 101 patients with OL-DES who underwent PCI between 1st July 2013 to 31st December 2016. The primary endpoint was target lesion failure (TLF) at two years, defined as a composite of cardiac mortality, target vessel myocardial infarction and target lesion revascularization.

Results: Mean age was 60.8 ± 10.5 years for SL-DES group and 60.5 ± 11.9 years in the OL-DES group. SL-DES has longer mean lesion length as compared to OL-DES (43.1 ± 3.7 mm vs. 41.83 ± 2.3 mm p = 0.003). There was no difference in TLF at two years between SL-DES and OL-DES (5.3% vs. 6.4%, adjusted odds ratio 1.43, 95% CI 0.50-4.11). There was one case of probable ST in each group. Contrast volume usage was lower for SL-DES than OL-DES in patients who underwent single vessel PCI.

Conclusions: Treatment of very-long CAD showed comparable TLF at two years for SL-DES versus OL-DES. Our results suggest that both strategies are reasonable treatment options for patients with diffuse CAD.
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http://dx.doi.org/10.1016/j.carrev.2020.02.005DOI Listing
September 2020

Patients with acute and chronic coronary syndromes have elevated long-term thrombin generation.

J Thromb Thrombolysis 2020 Aug;50(2):421-429

Department of Cardiology, National University Heart Centre Singapore, NUHS, Singapore, Singapore.

Coronary artery disease is a leading cause of morbidity and mortality worldwide. Despite significant advances in revascularization strategies and antiplatelet therapy with aspirin and/or P2Y receptor antagonist, patients with acute coronary syndrome (ACS) continue to be at long-term risk of further cardiovascular events. Besides platelet activation, the role of thrombin generation (TG) in atherothrombotic complications is widely recognized. In this study, we hypothesized that there is an elevation of coagulation activation persists beyond 12 months in patients with ACS and chronic coronary syndrome (CCS) when compared with healthy controls. We measured TG profiles of patients within 72 h after percutaneous coronary intervention, at 6-month, 12-month and 24-month. Our results demonstrated that TG of patients with ACS (n = 114) and CCS (n = 40) were persistently elevated when compared to healthy individuals (n = 50) in peak thrombin (ACS 273.1 nM vs CCS 287.3 nM vs healthy 234.3 nM) and velocity index (ACS 110.2 nM/min vs CCS 111.0 nM/min vs healthy 72.9 nM/min) at 24-month of follow-up. Our results suggest a rationale for addition of anticoagulation to antiplatelet therapy in preventing long-term ischemic events after ACS. Further research could clarify whether the use of TG parameters to enable risk stratification of patients at heightened long-term procoagulant risk who may benefit most from dual pathway inhibition.
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http://dx.doi.org/10.1007/s11239-020-02066-yDOI Listing
August 2020

Building a Longitudinal National Integrated Cardiovascular Database - Lessons Learnt From SingCLOUD.

Circ Rep 2019 Dec 7;2(1):33-43. Epub 2019 Dec 7.

Cardiac Department, National University Hospital Singapore.

Real world data on clinical outcomes and quality of care for patients with coronary artery disease (CAD) are fragmented. We describe the rationale and design of the Singapore Cardiovascular Longitudinal Outcomes Database (SingCLOUD). We designed a health data grid to integrate clinical, administrative, laboratory, procedural, prescription and financial data from all public-funded hospitals and primary care clinics, which provide 80% of health care in Singapore. Here, we explain our approach to harmonize real-world data from diverse electronic medical and non-medical platforms to develop a robust and longitudinal dataset. We present pilot data on patients with myocardial infarction (MI) treated with percutaneous coronary intervention (PCI) between 2012 and 2014. The initial data set had 53,395 patients. Of these, 35,203 had CAD confirmed on coronary angiography, of whom 21,521 had PCI. Eventually, limiting to 2012-2014, 3,819 patients had MI with PCI, while 5,989 had MI. Compared with the quality improvement registry, Singapore Cardiac Data Bank, which had 189 fields for analysis, the SingCLOUD platform generated an additional 313 additional data fields, and was able to identify an additional 250 heart failure events, 664 major adverse cardiovascular events at 2 years, and low-density lipoprotein levels to 1 year for 3,747 patients. By integrating multiple incongruent data sources, SINGCLOUD enables in-depth analysis of real-world cardiovascular "big data".
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http://dx.doi.org/10.1253/circrep.CR-19-0106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929705PMC
December 2019

Shared reference materials harmonize lipidomics across MS-based detection platforms and laboratories.

J Lipid Res 2020 01 15;61(1):105-115. Epub 2019 Nov 15.

Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore; Departments of Biochemistry, Yong Loo Lin School of Medicine National University of Singapore, Singapore. Electronic address:

Quantitative MS of human plasma lipids is a promising technology for translation into clinical applications. Current MS-based lipidomic methods rely on either direct infusion (DI) or chromatographic lipid separation methods (including reversed phase and hydrophilic interaction LC). However, the use of lipid markers in laboratory medicine is limited by the lack of reference values, largely because of considerable differences in the concentrations measured by different laboratories worldwide. These inconsistencies can be explained by the use of different sample preparation protocols, method-specific calibration procedures, and other experimental and data-reporting parameters, even when using identical starting materials. Here, we systematically investigated the roles of some of these variables in multiple approaches to lipid analysis of plasma samples from healthy adults by considering: ) different sample introduction methods (separation vs. DI methods); ) different MS instruments; and ) between-laboratory differences in comparable analytical platforms. Each of these experimental variables resulted in different quantitative results, even with the inclusion of isotope-labeled internal standards for individual lipid classes. We demonstrated that appropriate normalization to commonly available reference samples (i.e., "shared references") can largely correct for these systematic method-specific quantitative biases. Thus, to harmonize data in the field of lipidomics, in-house long-term references should be complemented by a commonly available shared reference sample, such as NIST SRM 1950, in the case of human plasma.
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http://dx.doi.org/10.1194/jlr.D119000393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939597PMC
January 2020

Pneumococcal Pneumonia Resembling Acute Myocardial Infarction in an Adolescent Male.

Pediatr Infect Dis J 2020 01;39(1):81-84

From the Khoo Teck Puat National University Children's Medical Institute, National University Health System, Singapore.

Myocarditis is commonly associated with viruses. However, we present a novel case of a teenager with pneumococcal pneumonia and bacteremia complicated by myocarditis and rhabdomyolysis, presenting with features of acute ST-elevation myocardial infarction and cardiogenic shock. Physicians should be aware that Streptococcus pneumoniae infection, like Group A Streptococcus, can mimic acute myocardial infarction in young males without cardiovascular risk factors.
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http://dx.doi.org/10.1097/INF.0000000000002527DOI Listing
January 2020

Associations of osteopontin and NT-proBNP with circulating miRNA levels in acute coronary syndrome.

Physiol Genomics 2019 10 18;51(10):506-515. Epub 2019 Sep 18.

Duke Molecular Physiology Institute, Durham, North Carolina.

The genomic regulatory networks underlying the pathogenesis of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) are incompletely understood. As intermediate traits, protein biomarkers report on underlying disease severity and prognosis in NSTE-ACS. We hypothesized that integration of dense microRNA (miRNA) profiling with biomarker measurements would highlight potential regulatory pathways that underlie the relationships between prognostic biomarkers, miRNAs, and cardiovascular phenotypes. We performed miRNA sequencing using whole blood from 186 patients from the TRILOGY-ACS trial. Seven circulating prognostic biomarkers were measured: NH-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein, osteopontin (OPN), myeloperoxidase, growth differentiation factor 15, monocyte chemoattractant protein, and neopterin. We tested miRNAs for association with each biomarker with generalized linear models and controlled the false discovery rate at 0.05. Ten miRNAs, including known cardiac-related miRNAs 25-3p and 423-3p, were associated with NT-proBNP levels (min. = 7.5 × 10) and 48 miRNAs, including cardiac-related miRNAs 378a-3p, 20b-5p and 320a, -b, and -d, were associated with OPN levels (min. = 1.6 × 10). NT-proBNP and OPN were also associated with time to cardiovascular death, myocardial infarction (MI), or stroke in the sample. By integrating large-scale miRNA profiling with circulating biomarkers as intermediate traits, we identified associations of known cardiac-related and novel miRNAs with two prognostic biomarkers and identified potential genomic networks regulating these biomarkers. These results, highlighting plausible biological pathways connecting miRNAs with biomarkers and outcomes, may inform future studies seeking to delineate genomic pathways underlying NSTE-ACS outcomes.
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http://dx.doi.org/10.1152/physiolgenomics.00033.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054637PMC
October 2019

Nationalization of post-MI managed care: a worthy cause but not without its challenges.

Int J Cardiol 2019 12 14;296:28-29. Epub 2019 Aug 14.

Federal University of Sao Paulo State, Sao Paulo, Brazil; Heart Hospital, Sao Paulo, Brazil; Albert Einstein Hospital, Sao Paulo, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2019.08.027DOI Listing
December 2019

Screening and treatment of obstructive sleep apnea in acute coronary syndrome. A randomized clinical trial.

Int J Cardiol 2020 01 3;299:20-25. Epub 2019 Jul 3.

Department of Cardiology, National University Heart Center Singapore, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cardiovascular Research Institute, National University of Singapore, Singapore. Electronic address:

Background: We evaluated the effects of sleep-study guided multidisciplinary therapy (SGMT) of obstructive sleep apnoea (OSA) in patients presenting with acute coronary syndrome.

Methods: Eligible patients were randomized into (1) SGMT, comprised a sleep study during the index admission and continuous positive airway pressure and behavioral therapy for those with at least mild OSA or (2) standard therapy. The primary end point was the change in the plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level from baseline to the 7-month follow-up.

Results: A total of 159 patients completed the trial. Of the 70 patients randomized to SGMT, 21 (30%), 15 (22%) and 27 (39%) were diagnosed with mild, moderate and severe OSA, respectively. Continuous positive airway pressure and a positional pillow were prescribed to 57 (91%) and 6 (9%) patients with OSA. Although plasma NT-proBNP levels were lower after 7 months compared to the baseline, the levels did not differ significantly between the SGMT and standard therapy groups at baseline (579 ± 1117 vs. 611 ± 899 pg/dL, p = .851) or at 7 months (90 ± 167 vs. 93 ± 174 pg/dL, p = .996). The changes in NT-proBNP levels from baseline to 7 months were similar with SGMT and standard therapy (-489 vs. -518 pg/dL, p = .726). Similar findings were observed for the plasma ST2 and hs-CRP levels.

Conclusions: OSA screening and multifaceted treatment during the sub-acute phase of acute coronary syndrome did not further reduce the levels of cardiovascular biomarkers when compared with standard therapy.

Clinical Trial Registration: clinicaltrial.gov NCT02599298.
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http://dx.doi.org/10.1016/j.ijcard.2019.07.003DOI Listing
January 2020

Independent Predictors of Cardiac Mortality and Hospitalization for Heart Failure in a Multi-Ethnic Asian ST-segment Elevation Myocardial Infarction Population Treated by Primary Percutaneous Coronary Intervention.

Sci Rep 2019 07 11;9(1):10072. Epub 2019 Jul 11.

The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, London, United Kingdom.

We aimed to identify independent predictors of cardiac mortality and hospitalization for heart failure (HHF) from a real-world, multi-ethnic Asian registry [the Singapore Myocardial Infarction Registry] of ST-segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention. 11,546 eligible STEMI patients between 2008 and 2015 were identified. In-hospital, 30-day and 1-year cardiac mortality and 1-year HHF rates were 6.4%, 6.8%, 8.3% and 5.2%, respectively. From the derivation cohort (70% of patients), age, Killip class and cardiac arrest, creatinine, hemoglobin and troponin on admission and left ventricular ejection fraction (LVEF) during hospitalization were predictors of in-hospital, 30-day and 1-year cardiac mortality. Previous ischemic heart disease (IHD) was a predictor of in-hospital and 30-day cardiac mortality only, whereas diabetes was a predictor of 1-year cardiac mortality only. Age, previous IHD and diabetes, Killip class, creatinine, hemoglobin and troponin on admission, symptom-to-balloon-time and LVEF were predictors of 1-year HHF. The c-statistics were 0.921, 0.901, 0.881, 0.869, respectively. Applying these models to the validation cohort (30% of patients) showed good fit and discrimination (c-statistic 0.922, 0.913, 0.903 and 0.855 respectively; misclassification rate 14.0%, 14.7%, 16.2% and 24.0% respectively). These predictors could be incorporated into specific risk scores to stratify reperfused STEMI patients by their risk level for targeted intervention.
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http://dx.doi.org/10.1038/s41598-019-46486-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624280PMC
July 2019

Rationale and Design of the High Platelet Inhibition with Ticagrelor to Improve Left Ventricular Remodeling in Patients with ST-Segment Elevation Myocardial Infarction (HEALING-AMI) Trial.

Korean Circ J 2019 Jul 22;49(7):586-599. Epub 2019 Mar 22.

Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon, Korea.

Background And Objectives: Impaired recovery from left ventricular (LV) dysfunction is a major prognostic factor after myocardial infarction (MI). Because P2Y₁₂ receptor blockade inhibits myocardial injury, ticagrelor with off-target properties may have myocardial protection over clopidogrel. In animal models, ticagrelor vs. clopidogrel protects myocardium against reperfusion injury and improves remodeling after MI. We aimed to investigate the effect of ticagrelor on sequential myocardial remodeling process after MI.

Methods: High platelet inhibition with ticagrelor to improve LV remodeling in patients with ST-segment elevation MI (HEALING-AMI) is an investigator-initiated, randomized, open-label, assessor-blinded, multi-center trial done at 10 sites in Korea. Patients will be enrolled if they have ST-segment elevation MI (STEMI) treated with primary percutaneous coronary intervention and a planned duration of dual antiplatelet treatment of at least 6 months. Screened patients will be randomly assigned (1:1) using an internet-based randomization with a computer-generated blocking with stratification across study sites to either ticagrelor or clopidogrel treatment. The co-primary primary endpoints are LV remodeling index with three-dimensional echocardiography and the level of N-terminal prohormone B-type natriuretic peptide (NT-proBNP) at 6 months representing post-MI remodeling processes. Changes of LV end-systolic/diastolic volume indices and LV ejection fraction between baseline and 6-month follow-up will be also evaluated. Analysis is per protocol.

Conclusions: HEALING-AMI is testing the effect of ticagrelor in reducing adverse LV remodeling following STEMI. Our trial would show the benefit of ticagrelor vs. clopidogrel related to the recovery of post-MI LV dysfunction beyond potent platelet inhibition.

Trial Registration: ClinicalTrials.gov Identifier: NCT02224534.
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http://dx.doi.org/10.4070/kcj.2018.0415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597457PMC
July 2019
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