Publications by authors named "Heerajnarain Bulluck"

88 Publications

Association between smoking status and outcomes in myocardial infarction patients undergoing percutaneous coronary intervention.

Sci Rep 2021 Mar 19;11(1):6466. Epub 2021 Mar 19.

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

Smoking is one of the leading risk factors for cardiovascular diseases, including ischemic heart disease and hypertension. However, in acute myocardial infarction (AMI) patients, smoking has been associated with better clinical outcomes, a phenomenon termed the "smoker's paradox." Given the known detrimental effects of smoking on the cardiovascular system, it has been proposed that the beneficial effect of smoking on outcomes is due to age differences between smokers and non-smokers and is therefore a smoker's pseudoparadox. The aim of this study was to evaluate the association between smoking status and clinical outcomes in ST-segment elevation (STEMI) and non-STEMI (NSTEMI) patients treated by percutaneous coronary intervention (PCI), using a national multi-ethnic Asian registry. In unadjusted analyses, current smokers had better clinical outcomes following STEMI and NSTEMI. However, after adjusting for age, the protective effect of smoking was lost, confirming a smoker's pseudoparadox. Interestingly, although current smokers had increased risk for recurrent MI within 1 year after PCI in both STEMI and NSTEMI patients, there was no increase in mortality. In summary, we confirm the existence of a smoker's pseudoparadox in a multi-ethnic Asian cohort of STEMI and NSTEMI patients and report increased risk of recurrent MI, but not mortality, in smokers.
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http://dx.doi.org/10.1038/s41598-021-86003-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979717PMC
March 2021

Cardiac procedural myocardial injury, infarction, and mortality in patients undergoing elective percutaneous coronary intervention: a pooled analysis of patient-level data.

Eur Heart J 2021 Jan;42(4):323-334

The Hatter Cardiovascular Institute, University College London, London, UK.

Aims: The prognostic importance of cardiac procedural myocardial injury and myocardial infarction (MI) in chronic coronary syndrome (CCS) patients undergoing elective percutaneous coronary intervention (PCI) is still debated.

Methods And Results: We analysed individual data of 9081 patients undergoing elective PCI with normal pre-PCI baseline cardiac troponin (cTn) levels. Multivariate models evaluated the association between post-PCI elevations in cTn and 1-year mortality, while an interval analysis evaluated the impact of the size of the myocardial injury on mortality. Our analysis was performed in the overall population and also according to the type of cTn used [52.0% had high-sensitivity cTn (hs-cTn)]. Procedural myocardial injury, as defined by the Fourth Universal Definition of MI (UDMI) [post-PCI cTn elevation ≥1 × 99th percentile upper reference limit (URL)], occurred in 52.8% of patients and was not associated with 1-year mortality [adj odds ratio (OR), 1.35, 95% confidence interval (CI) (0.84-1.77), P = 0.21]. The association between post-PCI cTn elevation and 1-year mortality was significant starting ≥3 × 99th percentile URL. Major myocardial injury defined by post-PCI ≥5 × 99th percentile URL occurred in 18.2% of patients and was associated with a two-fold increase in the adjusted odds of 1-year mortality [2.29, 95% CI (1.32-3.97), P = 0.004]. In the subset of patients for whom periprocedural evidence of ischaemia was collected (n = 2316), Type 4a MI defined by the Fourth UDMI occurred in 12.7% of patients and was strongly associated with 1-year mortality [adj OR 3.21, 95% CI (1.42-7.27), P = 0.005]. We also present our results according to the type of troponin used (hs-cTn or conventional troponin).

Conclusion: Our analysis has demonstrated that in CCS patients with normal baseline cTn levels, the post-PCI cTn elevation of ≥5 × 99th percentile URL used to define Type 4a MI is associated with 1-year mortality and could be used to detect 'major' procedural myocardial injury in the absence of procedural complications or evidence of new myocardial ischaemia.
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http://dx.doi.org/10.1093/eurheartj/ehaa885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850039PMC
January 2021

T and Small Protrusion (TAP) vs Double-Kissing Crush Technique: Insights From In Vitro Models.

Cardiovasc Revasc Med 2021 Mar 10;24:11-17. Epub 2020 Sep 10.

National Heart Research Institute of Singapore, National Heart Centre Singapore, Singapore; Department of Biomedical Engineering, National University of Singapore, Singapore. Electronic address:

Background: Percutaneous coronary interventions on complex bifurcation lesions may require implantation of two stents to appropriately treat diffuse side-branch (SB) disease. Comparisons among different bifurcation stenting techniques are continuously attempted by various study designs (bench tests, computer simulations, clinical studies). Among different techniques, double kissing crush (DKC) represents the last evolution for "crushing" while T and small Protrusion (TAP) represents the evolution of "T stenting". Both techniques are actually gaining popularity, but head-to-head comparisons are lacking.

Methods And Results: Two last generation drug-eluting stents (Synergy™, Boston Scientific, MA, USA and Ultimaster™,Terumo Corp., Japan) were implanted in left main bifurcation bench models using TAP (n = 6 sets) and DKC (n = 6 sets) techniques. A peristaltic pump with fresh porcine blood was used to perfuse the blood through the silicone model at a flow rate of 200 ml/min for 4 min. Optical coherence tomography (OCT) was used to assess stent struts geometry and thrombus formation. SB cross sectional area as well as SB obstruction did not significantly differ between the two techniques. Numerical (but not statistically significant) differences were found in terms of malapposed struts (fewer with TAP) and floating struts (fewer with DKC). Thrombus formation after blood perfusion was similar between TAP and DKC technique (1.53 ± 1.12 vs. 1.20 ± 1.01 mm, p = 0.6).

Conclusion: The result of the present in-vitro study shows the absence of significant difference between TAP and DKC in terms of stent struts apposition and acute thrombus formation potential. Despite the completely different technical steps required, both techniques have similar performance according to such articulated pre-clinical evaluation. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?: Due to its limited complexity, T and Protrusion (TAP) technique is considered the to-go technique for bifurcation lesions with good long-term results. Recently, double kissing crush (DKC) technique has been gaining popularity and demonstrated promising results in randomized clinical trials. WHAT DOES THIS STUDY ADD?: This in-vitro bench test study provides a unique detailed OCT comparison and local hemodynamic environment analysis of the two techniques. HOW MIGHT THIS IMPACT ON CLINICAL PRACTICE?: New insights of acute thrombogenicity and computational flow model simulation may guide percutaneous therapeutic strategies of bifurcation lesions.
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http://dx.doi.org/10.1016/j.carrev.2020.09.013DOI Listing
March 2021

Cardioprotection for Acute MI in Light of the CONDI2/ERIC-PPCI Trial: New Targets Needed.

Interv Cardiol 2020 Apr 25;15:e13. Epub 2020 Aug 25.

Department of Cardiology, Norfolk and Norwich University Hospital Norwich, UK.

Protection against ischaemia-reperfusion injury after revascularisation in acute myocardial infarction remains an enigma. Many targets have been identified, but after the failure of the recent Effect of Remote Ischaemic Conditioning on Clinical Outcomes in ST-elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention (CONDI2/ERIC-PPCI) trial to show translation to clinical benefit, there is still no pharmacological or mechanical strategy that has translated to clinical practice. This article addresses the results of the CONDI2/ERIC-PPCI trial in the context of previous studies of ischaemic conditioning, and then considers the prospects for other potential targets of cardioprotection. Finally, the authors examine the pitfalls and challenges in trial design for future investigation of cardioprotective strategies. In particular, this article highlights the need for careful endpoint and patient selection, as well as the need to pay attention to the biology of cardioprotection during the study.
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http://dx.doi.org/10.15420/icr.2020.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479528PMC
April 2020

Redefining Adverse and Reverse Left Ventricular Remodeling by Cardiovascular Magnetic Resonance Following ST-Segment-Elevation Myocardial Infarction and Their Implications on Long-Term Prognosis.

Circ Cardiovasc Imaging 2020 07 21;13(7):e009937. Epub 2020 Jul 21.

West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Clydebank, Scotland (H.B., D.C., M.M., M.C.P., H.E., S.H., S.W., M.L., A.M., K.G.O., C.B.).

Background: Cut off values for change in left ventricular end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) by cardiovascular magnetic resonance following ST-segment-elevation myocardial infarction have recently been proposed and 4 patterns of LV remodeling were described. We aimed to assess their long-term prognostic significance.

Methods: A prospective cohort of unselected patients with ST-segment-elevation myocardial infarction with paired acute and 6-month cardiovascular magnetic resonance, with the 5-year composite end point of all-cause death and hospitalization for heart failure was included. The prognosis of the following groups (group 1: reverse LV remodeling [≥12% decrease in LVESV]; group 2: no LV remodeling [changes in LVEDV and LVESV <12%]; group 3: adverse LV remodeling with compensation [≥12% increase in LVEDV only]; and group 4: adverse LV remodeling [≥12% increase in both LVESV and LVEDV]) was compared.

Results: Two hundred eighty-five patients were included with a median follow-up was 5.8 years. The composite end point occurred in 9.5% in group 1, 12.3% in group 2, 7.1% in group 3, and 24.2% in group 4. Group 4 had significantly higher cumulative event rates of the composite end point (log-rank test, =0.03) with the other 3 groups showing similar cumulative event rates (log-rank test, =0.51). Cox proportional hazard for group 2 (hazard ratio, 1.3 [95% CI, 0.6-3.1], =0.53) and group 3 (hazard ratio, 0.6 [95% CI, 0.2-2.3], =0.49) were not significantly different but was significantly higher in group 4 (hazard ratio, 3.0 [95% CI, 1.2-7.1], =0.015) when compared with group 1.

Conclusions: Patients with ST-segment-elevation myocardial infarction developing adverse LV remodeling at 6 months, defined as ≥12% increase in both LVESV and LVEDV by cardiovascular magnetic resonance, was associated with worse long-term clinical outcomes than those with adverse LV remodeling with compensation, reverse LV remodeling, and no LV remodeling, with the latter 3 groups having similar outcomes in a cohort of stable reperfused patients with ST-segment-elevation myocardial infarction. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850.
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http://dx.doi.org/10.1161/CIRCIMAGING.119.009937DOI Listing
July 2020

The Lipid Paradox is present in ST-elevation but not in non-ST-elevation myocardial infarction patients: Insights from the Singapore Myocardial Infarction Registry.

Sci Rep 2020 04 22;10(1):6799. Epub 2020 Apr 22.

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

Lowering low-density lipoprotein (LDL-C) and triglyceride (TG) levels form the cornerstone approach of cardiovascular risk reduction, and a higher high-density lipoprotein (HDL-C) is thought to be protective. However, in acute myocardial infarction (AMI) patients, higher admission LDL-C and TG levels have been shown to be associated with better clinical outcomes - termed the 'lipid paradox'. We studied the relationship between lipid profile obtained within 72 hours of presentation, and all-cause mortality (during hospitalization, at 30-days and 12-months), and rehospitalization for heart failure and non-fatal AMI at 12-months in ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) patients treated by percutaneous coronary intervention (PCI). We included 11543 STEMI and 8470 NSTEMI patients who underwent PCI in the Singapore Myocardial Infarction Registry between 2008-2015. NSTEMI patients were older (60.3 years vs 57.7 years, p < 0.001) and more likely to be female (22.4% vs 15.0%, p < 0.001). In NSTEMI, a lower LDL-C was paradoxically associated with worse outcomes for death during hospitalization, within 30-days and within 12-months (all p < 0.001), but adjustment eliminated this paradox. In contrast, the paradox for LDL-C persisted for all primary outcomes after adjustment in STEMI. For NSTEMI patients, a lower HDL-C was associated with a higher risk of death during hospitalization but in STEMI patients a lower HDL-C was paradoxically associated with a lower risk of death during hospitalization. For this endpoint, the interaction term for HDL-C and type of MI was significant even after adjustment. An elevated TG level was not protective after adjustment. These observations may be due to differing characteristics and underlying pathophysiological mechanisms in NSTEMI and STEMI.
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http://dx.doi.org/10.1038/s41598-020-63825-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176706PMC
April 2020

Chronic remote ischemic conditioning for cardiovascular protection.

Cond Med 2019 Aug;2(4):164-169

National Heart Centre Singapore, Singapore.

New treatments are needed to prevent adverse left ventricular remodelling following acute myocardial infarction (AMI), in order to prevent heart failure and improve clinical outcomes following AMI. Remote ischemic conditioning (RIC) using transient limb ischemia and reperfusion has been reported to reduce myocardial infarct (MI) size in AMI patients treated by primary percutaneous coronary intervention, and whether it can improve clinical outcomes is currently being investigated. Interestingly, repeated daily episode of limb RIC (termed 'chronic remote ischemic conditioning', or CRIC) has been shown in experimental and clinical studies to confer beneficial effects on post-AMI cardiac remodelling and chronic heart failure. In addition, the beneficial effects of CRIC extend to vascular function, peripheral arterial disease and stroke. In this review article, we focus on the therapeutic potential of CRIC as a strategy for cardiovascular protection and for improving clinical outcomes in patients with cardiovascular disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169952PMC
August 2019

Impact of time of onset of symptom of ST-segment elevation myocardial infarction on 1-year rehospitalization for heart failure and mortality.

Am Heart J 2020 06 19;224:1-9. Epub 2020 Mar 19.

National Heart Centre Singapore, Singapore, Singapore; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, Singapore, Singapore; The Hatter Cardiovascular Institute, University College London, London, UK; Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan; Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore; Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Nuevo Leon, Mexico. Electronic address:

Circadian patterns in ST-segment elevation myocardial infarction (STEMI) patients have been previously reported, but little is known about the impact of time dependence of symptom onset on long-term prognosis. Our study population consisted of 11,731 STEMI patients treated by primary percutaneous coronary intervention (PPCI), enrolled in the Singapore Myocardial Infarction Registry (SMIR). Analysis of STEMI incidence trends over the 24-hour period showed the highest rate of symptom onset in the morning, with the peak incidence at 09:00 am. Patients with symptom onset in between 00:00 am-5:59 am showed the highest prevalence of diabetes (P = .010) and anterior STEMI (P < .001) and had the longest ischemic time (P < .001). After adjusting for confounders, we found an association between time of symptom onset of STEMI and rehospitalization for heart failure (HF) at 1 year, with symptom onset between 06:00 pm-11:59 pm and 00:00 am-05:59 am having an estimated 30% to 50% higher risk of rehospitalization for HF at 1 year. Moreover, symptom onset remained a predictor of worse prognosis only in the subgroup of patients with symptoms lasting longer than 120 minutes. The results of this study demonstrate for the first time that rehospitalization for HF in STEMI patients treated with PPCI has a dependence on the time of onset of symptoms, with prolonged ischemia time playing a pivotal role. This may be an additional risk factor to identify those who warrant closer monitoring and more rigorous optimization of their treatment at follow-up, to improve their outcomes.
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http://dx.doi.org/10.1016/j.ahj.2020.03.011DOI Listing
June 2020

Is there a role for remote ischemic conditioning in preventing 5-fluorouracil-induced coronary vasospasm?

Cond Med 2019 Oct;2(5):204-212

National Heart Centre Singapore, Singapore.

Cardiac ischemia associated with chemotherapy has been linked to several anti-neoplastic agents and is multifactorial in etiology. Coronary artery vasospasm is one of the most commonly reported effects of cancer therapy that can lead to myocardial ischemia or infarction. The chemotherapy agent 5-fluorouracil (5-FU) or its oral pro-drug capecitabine can result in coronary vascular endothelial dysfunction causing coronary artery spasm, and possibly coronary thrombosis. These drugs have also been shown to be associated with myocardial infarction, malignant ventricular arrhythmias, heart failure, cardiogenic shock, and sudden death. The proposed mechanisms underlying cardiotoxicity induced by 5-FU are vascular endothelial damage followed by thrombus formation, ischemia secondary to coronary artery vasospasm, direct toxicity on myocardium, and thrombogenicity. There remains a pressing need to discover novel and effective therapies that can prevent or ameliorate 5-FU associated cardiotoxicity. To this point, promising overlap has been observed between proposed remote ischemic conditioning (RIC) cardioprotective mechanisms and 5FU-associated cardiotoxic cellular pathways. RIC, in which transient episodes of limb ischemia and reperfusion (induced by inflations and deflations of a pneumatic cuff placed on the upper arm or thigh), confer both cardioprotective and vasculoprotective effects, and may therefore prevent 5-FU coronary artery spasm/cardiotoxicity. In this review, we will be discussing the following potentially therapeutic aspects of RIC in ameliorating 5-FU associated cardiotoxicity: sequential phases of 5-FU cardiotoxicity as possible targets for dual windows of cardioprotection characteristic of RIC; protective effects of RIC on endothelial function and microvasculature in relation to 5-FU induced endothelial dysfunction/microvascular dysfunction; reduction in platelet activation by RIC in the context of 5-FU induced thrombogenicity; and the utility of improvement in mitochondrial function conferred by RIC in 5-FU induced cellular toxicity secondary to mitochondrial dysfunction.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055861PMC
October 2019

Myocardial Edema, Myocyte Injury, and Disease Severity in Fabry Disease.

Circ Cardiovasc Imaging 2020 03 2;13(3):e010171. Epub 2020 Mar 2.

Institute of Cardiovascular Science, University College London, United Kingdom (J.B.A., S.N., M.A., K.K., G.C., T.K., J.C.M.).

Background Cardiovascular magnetic resonance can demonstrate myocardial processes in Fabry disease (FD), such as low native T1 (sphingolipid storage) and late gadolinium enhancement (LGE, scar). Recently, high T2 (edema) has been observed in the basal inferolateral wall along with troponin elevation. We hypothesized that edema and myocyte injury would be chronically associated and have electrical, mechanical, and disease associations in FD. Methods A prospective international multicenter study was conducted on 186 consecutive FD patients (45.2±1.1 years, 58% females). Additionally, 28 patients with hypertrophic cardiomyopathy, 30 with chronic myocardial infarction and 59 healthy volunteers were included. All study participants underwent comprehensive cardiovascular magnetic resonance with T1 and T2 mapping, cines, and LGE imaging. Results LGE in the basal inferolateral wall in FD had T2 elevation (FD 58.2±5.0 ms versus hypertrophic cardiomyopathy 55.6±4.3 ms, chronic myocardial infarction 53.7±3.4 ms and healthy volunteers 48.9±2.5 ms, <0.001), but when LGE was present there was also global T2 elevation (53.1±2.9 versus 50.6±2.2 ms, <0.001). Thirty-eight percent of FD patients had high troponin. The strongest predictor of increased troponin was high basal inferolateral wall T2 (odds ratio, 18.2 [95% CI, 3.7-90.9], <0.0001). Both T2 and troponin elevations were chronic over 1 year. High basal inferolateral wall T2 was associated with baseline global longitudinal strain impairment (=0.005) and electrocardiographic abnormalities (long PR, complete bundle branch block, left ventricular hypertrophy voltage criteria, long QTc, and T-wave inversion, all <0.05) and predicted clinical worsening after 1 year (Fabry stabilization index >20%, =0.034). Conclusions LGE in Fabry has chronic local T2 elevation that is strongly associated with chronic troponin elevation. In addition, there is slight global T2 elevation. Both are associated with ECG and mechanical changes and clinical worsening over 1 year.
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http://dx.doi.org/10.1161/CIRCIMAGING.119.010171DOI Listing
March 2020

Effect of remote ischemic preConditioning on liver injury in patients undergoing liver resection: the ERIC-LIVER trial.

HPB (Oxford) 2020 Sep 30;22(9):1250-1257. Epub 2020 Jan 30.

Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore; National Heart Research Institute Singapore, National Heart Centre, Singapore; Yong Loo Lin School of Medicine, National University Singapore, Singapore; The Hatter Cardiovascular Institute, University College London, London, UK; Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan; Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Nuevo Leon, Mexico. Electronic address:

Objective: Novel hepatoprotective strategies are needed to improve clinical outcomes during liver surgery. There is mixed data on the role of remote ischemic preconditioning (RIPC). We investigated RIPC in partial hepatectomy for primary hepatocellular carcinoma (HCC).

Methods: This was a Phase II, single-center, sham-controlled, randomized controlled trial (RCT). The primary hypothesis was that RIPC would reduce acute liver injury following surgery indicated by serum alanine transferase (ALT) 24 h following hepatectomy in patients with primary HCC, compared to sham. Patients were randomized to receive either four cycles of 5 min/5 min arm cuff inflation/deflation immediately prior to surgery, or sham. Secondary endpoints included clinical, biochemical and pathological outcomes. Liver function measured by Indocyanine Green pulse densitometry was performed in a subset of patients.

Results: 24 and 26 patients were randomized to RIPC and control groups respectively. The groups were balanced for baseline characteristics, except the duration of operation was longer in the RIPC group. Median ALT at 24 h was similar between groups (196 IU/L IQR 113.5-419.5 versus 172.5 IU/L IQR 115-298 respectively, p = 0.61). Groups were similar in secondary endpoints.

Conclusion: This RCT did not demonstrate beneficial effects with RIPC on serum ALT levels 24 h after partial hepatectomy.
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http://dx.doi.org/10.1016/j.hpb.2019.12.002DOI Listing
September 2020

Periprocedural elevated myocardial biomarkers and clinical outcomes following elective percutaneous coronary intervention: a comprehensive dose-response meta-analysis of 44,972 patients from 24 prospective studies.

EuroIntervention 2020 Mar;15(16):1444-1450

Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Aims: The optimal cut-off value of isolated cardiac biomarker elevation for defining prognostically important percutaneous coronary intervention (PCI)-related myocardial injury is not known. We performed a meta-analysis to evaluate the dose-response relationship between isolated cardiac biomarker elevations and the risk of all-cause mortality following elective PCI.

Methods And Results: Twenty-four prospective studies (44,972 patients) were included. Patients with an isolated elevation of cardiac biomarkers had an increased risk of all-cause mortality when compared to those with no elevations (cardiac troponin I: odds ratio [OR] 1.42, 95% confidence interval [CI]: 1.19-1.69; creatine kinase-MB isoenzyme [CK-MB]: OR 1.43, 95% CI: 1.19-1.70). For the dose-response analysis, elevations of cardiac troponin I >3x or CK-MB >1x the 99th percentile upper reference limit (URL) were associated with increased mortality (cardiac troponin I: OR 1.51, 95% CI: 1.05-2.17; CK-MB: OR 1.25, 95% CI: 1.05-1.48). The pooled OR of mortality for each 3xURL increment of cardiac troponin I or CK-MB was 1.33 (95% CI: 1.15-1.53) and 1.38 (95% CI: 1.30-1.47).

Conclusions: We found that a positive dose-response relationship between isolated cardiac troponin I and CK-MB with all-cause mortality and elevated cardiac troponin I >3x or CK-MB >1x the 99th percentile URL was associated with an increased risk of mortality.
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http://dx.doi.org/10.4244/EIJ-D-19-00737DOI Listing
March 2020

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

Lancet 2019 10 6;394(10207):1415-1424. Epub 2019 Sep 6.

The Hatter Cardiovascular Institute, University College London, London, UK. Electronic address:

Background: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months.

Methods: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed.

Findings: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed.

Interpretation: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI.

Funding: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden.
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http://dx.doi.org/10.1016/S0140-6736(19)32039-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891239PMC
October 2019

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

Optimized Treatment of ST-Elevation Myocardial Infarction.

Circ Res 2019 07 3;125(2):245-258. Epub 2019 Jul 3.

University Heart Center Lübeck, Medical Clinic II (Cardiology/Angiology/Intensive Care Medicine) and German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany (T.S., I.E.).

Primary percutaneous coronary intervention is nowadays the preferred reperfusion strategy for patients with acute ST-segment-elevation myocardial infarction, aiming at restoring epicardial infarct-related artery patency and achieving microvascular reperfusion as early as possible, thus limiting the extent of irreversibly injured myocardium. Yet, in a sizeable proportion of patients, primary percutaneous coronary intervention does not achieve effective myocardial reperfusion due to the occurrence of coronary microvascular obstruction (MVO). The amount of infarcted myocardium, the so-called infarct size, has long been known to be an independent predictor for major adverse cardiovascular events and adverse left ventricular remodeling after myocardial infarction. Previous cardioprotection studies were mainly aimed at protecting cardiomyocytes and reducing infarct size. However, several clinical and preclinical studies have reported that the presence and extent of MVO represent another important independent predictor of adverse left ventricular remodeling, and recent evidences support the notion that MVO may be more predictive of major adverse cardiovascular events than infarct size itself. Although timely and complete reperfusion is the most effective way of limiting myocardial injury and subsequent ventricular remodeling, the translation of effective therapeutic strategies into improved clinical outcomes has been largely disappointing. Of importance, despite the presence of a large number of studies focused on infarct size, only few cardioprotection studies addressed MVO as a therapeutic target. In this review, we provide a detailed summary of MVO including underlying causes, diagnostic techniques, and current therapeutic approaches. Furthermore, we discuss the hypothesis that simultaneously addressing infarct size and MVO may help to translate cardioprotective strategies into improved clinical outcome following ST-segment-elevation myocardial infarction.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315344DOI Listing
July 2019

Interrogation of the infarcted and salvaged myocardium using multi-parametric mapping cardiovascular magnetic resonance in reperfused ST-segment elevation myocardial infarction patients.

Sci Rep 2019 06 21;9(1):9056. Epub 2019 Jun 21.

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

We used multi-parametric cardiovascular magnetic resonance (CMR) mapping to interrogate the myocardium following ST-segment elevation myocardial infarction (STEMI). Forty-eight STEMI patients underwent CMR at 4 ± 2 days. One matching short-axis slice of native T1 map, T2 map, late gadolinium enhancement (LGE), and automated extracellular volume fraction (ECV) maps per patient were analyzed. Manual regions-of-interest were drawn within the infarcted, the salvaged and the remote myocardium. A subgroup analysis was performed in those without MVO and with ≤75% transmural extent of infarct. For the whole cohort, T1, T2 and ECV in both the infarcted and the salvaged myocardium were significantly higher than in the remote myocardium. T1 and T2 could not differentiate between the salvaged and the infarcted myocardium, but ECV was significantly higher in the latter. In the subgroup analysis of 15 patients, similar findings were observed for T1 and T2. However, there was only a trend towards ECV being higher than ECV. In the clinical setting, current native T1 and T2 methods with the specific voxel sizes at 1.5 T could not differentiate between the infarcted and salvaged myocardium, whereas ECV could differentiate between the two. ECV was also higher in the salvaged myocardium when compared to the remote myocardium.
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http://dx.doi.org/10.1038/s41598-019-45449-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588689PMC
June 2019

Mineralocorticoid receptor antagonist pre-treatment and early post-treatment to minimize reperfusion injury after ST-elevation myocardial infarction: The MINIMIZE STEMI trial.

Am Heart J 2019 05 20;211:60-67. Epub 2019 Feb 20.

Hatter Cardiovascular Institute, London, United Kingdom; Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom; The National Institute of Health Research University College London Hospitals Biomedical Research Centre, London, United Kingdom; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, Singapore; Yong Loo Lin School of Medicine, National University Singapore, Singapore; Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Nuevo Leon, Mexico. Electronic address:

Background: Mineralocorticoid receptor antagonist (MRA) therapy has been shown to prevent adverse left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients with heart failure. Whether initiating MRA therapy prior to primary percutaneous coronary intervention (PPCI) accrues additional benefit of reducing myocardial infarct size and preventing adverse LV remodeling is not known. We aimed to investigate whether MRA therapy initiated prior to reperfusion reduces myocardial infarct (MI) size and prevents adverse LV remodeling in STEMI patients.

Methods: STEMI patients presenting within 12 hours and with a proximal coronary artery occlusion with Thrombolysis In Myocardial Infarction flow grade 0 were consented and randomized to either an intravenous bolus of potassium canrenoate, followed by oral spironolactone for 3 months or matching placebo. The primary endpoint was MI size by cardiovascular magnetic resonance at 3 months.

Results: Sixty-seven patients completed the study. There was no significant difference in the final MI size at 3 months between the 2 groups (placebo: 17 ± 11%, MRA: 16 ± 10%, P = .574). There was also no difference in acute MI size (26 ± 16% versus 23 ± 14%, P = .425) or myocardial salvage (26 ± 12% versus 24 ± 8%, P = .456). At follow-up, there was a trend towards an improvement in LVEF (placebo: 49 ± 8%, MRA: 54 ± 11%, P = .053), and the MRA group had significantly greater percentage decrease in LVEDV (mean difference: -12.2 (95% CI -20.3 to -4.4)%, P = .003) and LVESV (mean difference: -18.2 (95% CI -30.1 to -6.3)%, P = .003).

Conclusion: This pilot study showed no benefit of MRA therapy in reducing MI size in STEMI patients when initiated prior to reperfusion, but there was an improvement in LV remodeling at 3 months. Adequately powered studies are warranted to confirm these findings.
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http://dx.doi.org/10.1016/j.ahj.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483973PMC
May 2019

Defining a 'frequent admitter' phenotype among patients with repeat heart failure admissions.

Eur J Heart Fail 2019 03 13;21(3):311-318. Epub 2018 Dec 13.

National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.

Aims: We aimed to identify a 'frequent admitter' phenotype among patients admitted for acute decompensated heart failure (HF).

Methods And Results: We studied 10 363 patients in a population-based prospective HF registry (2008-2012), segregated into clusters based on their 3-year HF readmission frequency trajectories. Using receiver-operating characteristic analysis, we identified the index year readmission frequency threshold that most accurately predicts HF admission frequency clusters. Two clusters of HF patients were identified: a high frequency cluster (90.9%, mean 2.35 ± 3.68 admissions/year) and a low frequency cluster (9.1%, mean 0.50 ± 0.81 admission/year). An index year threshold of two admissions was optimal for distinguishing between clusters. Based on this threshold, 'frequent admitters', defined as patients with ≥ 2 HF admissions in the index year (n = 2587), were of younger age (68 ± 13 vs 69 ± 13 years), more often male (58% vs. 54%), smokers (38.4% vs. 34.4%) and had lower left ventricular ejection fraction (37 ± 17 vs. 41 ± 17%) compared to 'non-frequent admitters' (< 2 HF admissions in the index year; n = 7776) (all P < 0.001). Despite similar rates of advanced care utilization, frequent admitters had longer length of stay (median 4.3 vs. 4.0 days), higher annual inpatient costs (€ 7015 vs. € 2967) and higher all-cause mortality at 3 years compared to the non-frequent admitters (adjusted odds ratio 2.33, 95% confidence interval 2.11-2.58; P < 0.001).

Conclusion: 'Frequent admitters' have distinct clinical characteristics and worse outcomes compared to non-frequent admitters. This study may provide a means of anticipating the HF readmission burden and thereby aid in healthcare resource distribution relative to the HF admission frequency phenotype.
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http://dx.doi.org/10.1002/ejhf.1348DOI Listing
March 2019

Platelet inhibition to target reperfusion injury trial: Rationale and study design.

Clin Cardiol 2019 Jan 17;42(1):5-12. Epub 2018 Dec 17.

The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, London, UK.

Background: In ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI), current oral P2Y12 platelet inhibitors do not provide maximal platelet inhibition at the time of reperfusion. Furthermore, administration of cangrelor prior to reperfusion has been shown in pre-clinical studies to reduce myocardial infarct (MI) size. Therefore, we hypothesize that cangrelor administered prior to reperfusion in STEMI patients will reduce the incidence of microvascular obstruction (MVO) and limit MI size in STEMI patients treated with PPCI.

Methods: The platelet inhibition to target reperfusion injury (PITRI) trial, is a phase 2A, multi-center, double-blinded, randomized controlled trial, in which 210 STEMI patients will be randomized to receive either an intravenous (IV) bolus of cangrelor (30 μg/kg) followed by a 120-minute infusion (4 μg/kg/min) or matching saline placebo, initiated prior to reperfusion (NCT03102723).

Results: The study started in October 2017 and the anticipated end date would be July 2020. The primary end-point will be MI size quantified by cardiovascular magnetic resonance (CMR) on day 3 post-PPCI. Secondary endpoints will include markers of reperfusion, incidence of MVO, MI size, and adverse left ventricular remodeling at 6 months, and major adverse cardiac and cerebrovascular events.

Summary: The aim of the PITRI trial is to assess whether cangrelor administered prior to reperfusion would reduce acute MI size and MVO, as assessed by CMR.
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http://dx.doi.org/10.1002/clc.23110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436500PMC
January 2019

Incidence and predictors of left ventricular thrombus by cardiovascular magnetic resonance in acute ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention: a meta-analysis.

J Cardiovasc Magn Reson 2018 11 8;20(1):72. Epub 2018 Nov 8.

The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, London, UK.

Introduction: The incidence of left ventricular (LV) thrombus formation in ST-segment elevation myocardial infarction (STEMI) patients in the current era of primary percutaneous coronary intervention (PCI) is not well established. We performed a meta-analysis to assess the actual incidence and predictors of LV thrombus by cardiovascular magnetic resonance (CMR) in STEMI treated by primary PCI.

Methods: We searched MEDLINE and EMBASE databases up to February 2018. We included all studies published as a full-text article, reporting the incidence of LV thrombus by CMR within 1 month following acute STEMI in patients treated by primary PCI. A binary random-effects model was used to estimate the pooled incidence of LV thrombus. The diagnostic performance of transthoracic echocardiography (TTE) as compared with CMR was pooled to obtain the sensitivity and specificity of TTE with CMR as the gold standard. Embolic and bleeding complications of LV thrombus were also evaluated.

Results: Ten studies were included in the meta-analysis. The incidence of LV thrombus by CMR in all-comer STEMI patients (n = 2072) was 6.3% with 96% of LV thrombus occurring in those with anterior STEMI (12.2% incidence). When only anterior STEMI with LVEF< 50% were considered (n = 447), the incidence of LV thrombus was 19.2%. Compared with CMR, the sensitivity of TTE to detect LV thrombus was 29% with a specificity of 98%. The sensitivity of TTE increased to 70% in those with anterior STEMI and reduced LVEF. LV thrombus resolved in 88% of cases by 3 to 6 months. After 1-2 years follow-up, the embolic complication rate was similar at 1.5% (P = 0.25) but the bleeding complication rate was significantly higher (8.8% versus 0.5%, P < 0.001) in the LV thrombus group on triple therapy when compared to the no LV thrombus group on dual antiplatelet therapy.

Conclusion: In the primary PCI era, CMR detection of an LV thrombus post-STEMI remains high with incidence of nearly 20% in anterior STEMI with depressed LVEF. Patients with LV thrombus treated by triple therapy had similar embolic complications but higher bleeding complications than those with no LV thrombus treated with dual antiplatelet therapy. A 3 month follow-up CMR scan to guide anticoagulation duration might help mitigate bleeding risk.
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http://dx.doi.org/10.1186/s12968-018-0494-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222991PMC
November 2018

Remote ischemic conditioning in ST-segment elevation myocardial infarction - an update.

Cond Med 2018 Aug;1(5):13-22

Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom.

Acute myocardial infarction (AMI) and the heart failure (HF) that often results are among the leading causes of death and disability in the world. As such, novel strategies are required to protect the heart against the detrimental effects of acute ischemia/reperfusion injury (IRI), in order to reduce myocardial infarct (MI) size and prevent the onset of HF. The endogenous cardioprotective strategy of remote ischemic conditioning (RIC), in which cycles of brief ischemia and reperfusion are applied to a tissue or organ away from the heart, has been reported in experimental studies to reduce MI size in animal models of acute IRI. In the clinical setting, RIC can be induced by simply inflating and deflating a cuff placed on the upper arm or thigh to induce brief cycles of ischemia and reperfusion, a strategy which has been shown to reduce MI size in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI). The results of the ongoing CONDI2/ERIC-PPCI trial are eagerly awaited, and will provide definitive answers with regards to the cardioprotective effect and clinical outcome benefits of RIC in STEMI.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191186PMC
August 2018

Optimizing the Detection of Left Ventricular Thrombus Following Acute Myocardial Infarction in the Current Era.

JAMA Cardiol 2018 11;3(11):1128-1129

Cardiovascular and Metabolic Disorders Program, Duke-National University Singapore Medical School, Singapore.

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http://dx.doi.org/10.1001/jamacardio.2018.3136DOI Listing
November 2018

Modulating NAD metabolism to prevent acute kidney injury.

Nat Med 2018 09;24(9):1306-1307

The Hatter Cardiovascular Institute, University College London, London, UK.

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http://dx.doi.org/10.1038/s41591-018-0181-9DOI Listing
September 2018

Percutaneous coronary intervention of saphenous vein grafts: where do we stand?

EuroIntervention 2018 06;14(2):142-143

Norfolk and Norwich University Hospital, Norwich, United Kingdom.

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http://dx.doi.org/10.4244/EIJV14I2A22DOI Listing
June 2018