IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria: guidelines of the EU-CARDIOPROTECTION COST Action

Cardioprotection; Drug development; InfarctionCardioprotección; Desarrollo de fármacos; InfartoCardioprotecció; Desenvolupament de fàrmacs; InfartAcute myocardial infarction (AMI) and the heart failure (HF) which may follow are among the leading causes of death and disability worldwide. As such, new therapeutic interventions are still needed to protect the heart against acute ischemia/reperfusion injury to reduce myocardial infarct size and prevent the onset of HF in patients presenting with AMI. However, the clinical translation of cardioprotective interventions that have proven to be beneficial in preclinical animal studies, has been challenging. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic in vivo preclinical assessment of the efficacy of promising cardioprotective interventions prior to their clinical evaluation. To address this, we propose an in vivo set of step-by-step criteria for IMproving Preclinical Assessment of Cardioprotective Therapies (‘IMPACT’), for investigators to consider adopting before embarking on clinical studies, the aim of which is to improve the likelihood of translating novel cardioprotective interventions into the clinical setting for patient benefit.This article is based on the work from COST Action EU-CARDIOPROTECTION CA16225 supported by COST (European Cooperation in Science and Technology). DJH is supported by the Duke-National University Singapore Medical School, Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/0011/2017) and Collaborative Centre Grant scheme (NMRC/CGAug16C006). SL is supported by grants from the South African Department of Science and Technology and the South African National Research Foundation. SMD is supported by grants from the British Heart Foundation (PG/19/51/34493 and PG/16/85/32471). GH is supported by the German Research Foundation (SFB 1116 B8). MRM is supported by the Spanish Institute of Health Carlos III (FIS PI19/01196 and CIBER-CV). RS is supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [Project number 268555672—SFB 1213, Project B05]. PF is supported by the National Research, Development and Innovation Office of Hungary (Research Excellence Program—TKP, National Heart Program NVKP 16-1-2016-0017) and by the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the Therapeutic Development thematic program of the Semmelweis University

25 year trends in first time hospitalisation for acute myocardial infarction, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity: a Danish nationwide cohort study

Objectives To examine 25 year trends in first time hospitalisation for acute myocardial infarction in Denmark, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity

Effect of remote ischaemic conditioning on platelet reactivity and endogenous fibrinolysis in ST-elevation myocardial infarction- a substudy of the CONDI-2/ERIC4 PPCI randomised controlled trial

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly citedBackground: Remote ischaemic conditioning (RIC) has been shown to reduce myocardial infarct size in animal models of myocardial infarction. Platelet thrombus formation is a critical determinant of outcome in ST-segment elevation myocardial infarction (STEMI). Whether the beneficial effects of RIC are related to thrombotic parameters is unclear. Methods and Results: In a pre-specified substudy of the Effect of Remote Ischaemic Conditioning on clinical outcomes in STEMI patients undergoing Primary Percutaneous Coronary Intervention (ERIC-PPCI) trial, we assessed the effect of RIC on thrombotic status. Patients presenting with STEMI were randomised to immediate RIC consisting of an automated autoRICTM cuff on the upper arm inflated to 200mmHg for 5 minutes and deflated for 5 minutes for 4 cycles (n=53) or sham (n=47). Venous blood was tested at presentation, discharge (48 h) and 6-8 weeks, to assess platelet reactivity, coagulation and endogenous fibrinolysis using the Global Thrombosis Test and thromboelastography (TEG). Baseline thrombotic status was similar in the 2 groups. At discharge, there was some evidence that the time to in vitro thrombotic occlusion under high shear stress was longer with RIC compared to sham (454±105s vs. 403±105s; mean difference 50.1s; 95% confidence interval [CI] 93.7- 6.4, P=0.025), but this was no longer apparent at 6-8 weeks. There was no difference in clot formation or endogenous fibrinolysis between the study arms at any time-point. Conclusion: RIC may reduce platelet reactivity in the first 48h post-STEMI. Further research is needed to delineate mechanisms through which RIC may reduce platelet reactivity, and whether it may improve outcomes in patients with persistent high on-treatment platelet reactivity.Peer reviewedFinal Accepted Versio

Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning

Risc cardiovascular; Isquèmia/reperfusióCardiovascular risk; Ischemia/reperfusionRiesgo cardiovascular; Isquemia/reperfusiónPreconditioning, postconditioning, and remote conditioning of the myocardium enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and the potential to provide novel therapeutic paradigms for cardioprotection. While many signaling pathways leading to endogenous cardioprotection have been elucidated in experimental studies over the past 30 years, no cardioprotective drug is on the market yet for that indication. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic preclinical evaluation of promising cardioprotective therapies prior to their clinical evaluation, since ischemic heart disease in humans is a complex disorder caused by or associated with cardiovascular risk factors and comorbidities. These risk factors and comorbidities induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury and responses to cardioprotective interventions. Moreover, some of the medications used to treat these comorbidities may impact on cardioprotection by again modifying cellular signaling pathways. The aim of this article is to review the recent evidence that cardiovascular risk factors as well as comorbidities and their medications may modify the response to cardioprotective interventions. We emphasize the critical need for taking into account the presence of cardiovascular risk factors as well as comorbidities and their concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple comorbidities. Significance Statement Ischemic heart disease is a major cause of mortality; however, there are still no cardioprotective drugs on the market. Most studies on cardioprotection have been undertaken in animal models of ischemia/reperfusion in the absence of comorbidities; however, ischemic heart disease develops with other systemic disorders (e.g., hypertension, hyperlipidemia, diabetes, atherosclerosis). Here we focus on the preclinical and clinical evidence showing how these comorbidities and their routine medications affect ischemia/reperfusion injury and interfere with cardioprotective strategies.P.F. was supported by the National Research, Development and Innovation Office of Hungary (Research Excellence Program–TKP, National Heart Program NVKP 16-1-2016-0017) and by the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the Therapeutic Development thematic program of Semmelweis University. D.D. is supported by grants from National Institutes of Health National Heart, Lung, and Blood Institute [R01-HL136389, R01-HL131517, R01-HL089598, and R01-HL163277], the German Research Foundation [DFG, Do 769/4-1], the European Union (large-scale integrative project MAESTRIA, no. 965286). G.H. is supported by the German Research Foundation [SFB 1116 B8]. D.H. is supported by the Duke–NUS Signature Research Programme funded by the Ministry of Health, Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist–Senior Investigator scheme [NMRC/CSA-SI/0011/2017], Centre Grant [CGAug16M006], and Collaborative Centre Grant scheme [NMRC/CGAug16C006]. I.A. is supported from Boehringer-Ingelheim for the investigation of the effects of empagliflozin on the myocardium and from the European Union (ERDF) and Greek national funds through the Operational Program “Competitiveness, Entrepreneurship and Innovation,” under the call “RESEARCH – CREATE – INNOVATE” (project code: 5048539). S.M.D. acknowledges the support of the British Heart Foundation [PG/19/51/34493 and PG/16/85/32471]. S.L. is supported by the South African National Research Foundation and received COST Seed funding from the Department of Science and Innovation in South Africa. M.R-M. is supported by the Instituto de Salud Carlos III of the Spanish Ministry of Health [FIS-PI19-01196] and a grant from the Spanish Society of Cardiology [SEC/FEC-INV-BAS 217003]. C.J.Z. is supported by a grant from European Foundation for the Study of Diabetes (EFSD), a research grant from Boehringer-Ingelheim and an institutional grant from Amsterdam UMC Cardiovascular Research. R.S. is supported by Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) [Project number 268555672—SFB 1213, Project B05]

Diagnosing coronary artery disease by sound analysis from coronary stenosis induced turbulent blood flow: diagnostic performance in patients with stable angina pectoris

Optimizing risk assessment may reduce use of advanced diagnostic testing in patients with symptoms suggestive of stable coronary artery disease (CAD). Detection of diastolic murmurs from post-stenotic coronary turbulence with an acoustic sensor placed on the chest wall can serve as an easy, safe, and low-cost supplement to assist in the diagnosis of CAD. The aim of this study was to evaluate the diagnostic accuracy of an acoustic test (CAD-score) to detect CAD and compare it to clinical risk stratification and coronary artery calcium score (CACS). We prospectively enrolled patients with symptoms of CAD referred to either coronary computed tomography or invasive coronary angiography (ICA). All patients were tested with the CAD-score system. Obstructive CAD was defined as more than 50 % diameter stenosis diagnosed by quantitative analysis of the ICA. In total, 255 patients were included and obstructive CAD was diagnosed in 63 patients (28 %). Diagnostic accuracy evaluated by receiver operating characteristic curves was 72 % for the CAD-score, which was similar to the Diamond–Forrester clinical risk stratification score, 79 % (p = 0.12), but lower than CACS, 86 % (p < 0.01). Combining the CAD-score and Diamond–Forrester score, AUC increased to 82 %, which was significantly higher than the standalone CAD-score (p < 0.01) and Diamond–Forrester score (p < 0.05). Addition of the CAD-score to the Diamond–Forrester score increased correct reclassification, categorical net-reclassification index = 0.31 (p < 0.01). This study demonstrates the potential use of an acoustic system to identify CAD. The combination of clinical risk scores and an acoustic test seems to optimize patient selection for diagnostic investigation.Danish National Business Innovation Fund and Acarix A/S

Cardioprotective effect of succinate dehydrogenase inhibition in rat hearts and human myocardium with and without diabetes mellitus

Abstract Ischemia reperfusion (IR) injury may be attenuated through succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL). Whether SDH inhibition yields protection in diabetic individuals and translates into human cardiac tissue remain unknown. In isolated perfused hearts from 24 weeks old male Zucker diabetic fatty (ZDF) and age matched non-diabetic control rats and atrial trabeculae from patients with and without diabetes, we compared infarct size, contractile force recovery and mitochondrial function. The cardioprotective effect of a 10 minutes DiMAL administration prior to global ischemia and ischemic preconditioning (IPC) was evaluated. In non-diabetic hearts exposed to IR, DiMAL 0.1 mM reduced infarct size compared to IR (55 ± 7% vs. 69 ± 6%, p < 0.05). Mitochondrial respiration was reduced by DiMAL 0.6 mM compared to sham and DiMAL 0.1 mM (p < 0.05). In diabetic hearts an increased concentration of DiMAL (0.6 mM) was required for protection compared to IR (64 ± 13% vs. 79 ± 8%, p < 0.05). Mitochondrial function remained unchanged. In trabeculae from humans without diabetes, IPC and DiMAL improved contractile force recovery compared to IR (43 ± 12% and 43 ± 13% vs. 23 ± 13%, p < 0.05) but in patients with diabetes only IPC provided protection compared to IR (51 ± 15% vs. 21 ± 8%, p < 0.05). Neither IPC nor DiMAL modulated mitochondrial respiration in patients. Cardioprotection by SDH inhibition is possible in human tissue, but depends on diabetes status. The narrow therapeutic range and discrepancy in respiration between experimental and human studies may limit clinical translation

Mortality Risk Among Heart Failure Patients With Depression:A Nationwide Population-Based Cohort Study

BACKGROUND: The prevalence of depression is 4‐ to 5‐fold higher in heart failure patients than in the general population. We examined the influence of depression on all‐cause mortality in patients with heart failure. METHODS AND RESULTS: Using Danish medical registries, this nationwide population‐based cohort study included all patients with a first‐time hospitalization for heart failure (1995–2014). All‐cause mortality risks and 19‐year mortality rate ratios were estimated based on Cox regression analysis, adjusting for age, sex, time period, comorbidity, and socioeconomic status. The analysis included 9636 patients with and 194 887 patients without a diagnosis of depression. Compared with patients without a history of depression, those with depression had higher 1‐year (36% versus 33%) and 5‐year (68% versus 63%) mortality risks. Overall, the adjusted mortality rate ratio was 1.03 (95% CI 1.01–1.06). Compared with no depression, the adjusted mortality rate ratios for mild, moderate, and severe depression, as defined by diagnostic codes, were 1.06 (95% CI 1.00–1.13), 1.03 (95% CI 0.99–1.08), and 1.02 (95% CI 0.96–1.09), respectively. In a subcohort of patients, the mortality rate ratios were modified by left ventricular ejection fraction, with adjusted mortality rate ratios of 1.17 (95% CI, 1.05–1.31) for ≤35%, 0.98 (95% CI 0.81–1.18) for 36% to 49%, and 0.96 (95% CI 0.74–1.25) for ≥50%. Results were consistent after adjustment for alcohol abuse and smoking. CONCLUSIONS: A history of depression was an adverse prognostic factor for all‐cause mortality in heart failure patients with left ventricular ejection fraction ≤35% but not for other heart failure patients

Ischaemia-reperfusion injury impairs tissue plasminogen activator release in man

AIMS: Ischaemia-reperfusion (IR) injury causes endothelium-dependent vasomotor dysfunction that can be prevented by ischaemic preconditioning. The effects of IR injury and preconditioning on endothelium-dependent tissue plasminogen activator (t-PA) release, an important mediator of endogenous fibrinolysis, remain unknown. METHODS AND RESULTS: Ischaemia-reperfusion injury (limb occlusion at 200 mmHg for 20 min) was induced in 22 healthy subjects. In 12 subjects, IR injury was preceded by local or remote ischaemic preconditioning (three 5 min episodes of ipsilateral or contralateral limb occlusion, respectively) or sham in a randomized, cross-over trial. Forearm blood flow (FBF) and endothelial t-PA release were assessed using venous occlusion plethysmography and venous blood sampling during intra-arterial infusion of acetylcholine (5-20 µg/min) or substance P (2-8 pmol/min). Acetylcholine and substance P caused dose-dependent increases in FBF (P&lt;0.05 for all). Substance P caused a dose-dependent increase in t-PA release (P&lt;0.05 for all). Acetylcholine and substanceP-mediated vasodilatation and substanceP-mediated t-PA release were impaired following IR injury (P&lt;0.05 for all). Neither local nor remote ischaemic preconditioning protected against the impairment of substance P-mediated vasodilatation or t-PA release. CONCLUSION: Ischaemia-reperfusion injury induced substanceP-mediated, endothelium-dependent vasomotor and fibrinolytic dysfunction in man that could not be prevented by ischaemic preconditioning. CLINICAL TRIAL REGISTRATION INFORMATION: Reference number: NCT00789243, URL: http://clinicaltrials.gov/ct2/show/NCT00789243?term=NCT00789243andrank=1

Evaluation of the relationship between hyperinsulinaemia and myocardial ischaemia/reperfusion injury in a rat model of depression

Major depression is associated with medical comorbidity such as ischaemic heart disease and diabetes but the underlying pathophysiological mechanisms remain unclear. The Flinders Sensitive Line (FSL) rat is a genetic animal model of depression exhibiting features similar to those of depressed individuals. The aim of the present study was to compare the myocardial responsiveness to ischaemia-reperfusion injury and effects of ischaemic preconditioning (IPC) in hearts from FSL rats using Sprague-Dawley (SD) rats as controls and to characterize differences in glucose metabolism and insulin sensitivity between the FSL and SD rats. Hearts were perfused in a Langendorff model and subjected or not to IPC before 40 minutes of global ischaemia followed by 120 minutes of reperfusion. Myocardial infarct size was found to be significantly larger in the FSL rats (I/R: 62.4±4.2 vs. 46.9±2.9%, P<0.05) than in the SD rats. IPC reduced the infarct size (P<0.01) and improved haemodynamic function (P<0.01) in both the FSL and the SD rats. No significant difference was found in blood glucose levels between the two groups measured after 12 hours of fasting but fasting plasma insulin (70.1±8.9 vs. 40.9±4.7 pmol/l, P<0.05) and HOMA (homeostatic model assessment) index (P<0.01) were significantly higher in the FSL rats compared to the SD rats. In conclusion, FSL rats had larger infarct sizes and were found to be hyperinsulinaemic compared to SD rats but seemed to have a maintained cardioprotective mechanism against ischaemia-reperfusion injury as IPC reduced infarct size in these rats. This animal model may be useful in future studies when examining the mechanisms that contribute to the cardiovascular complications associated with depression