Mariama Akodad

Interest of colchicine in the treatment of acute myocardial infarct responsible for heart failure in a mouse model

BACKGROUND Inflammation is deeply involved in the pathophysiology of ischemia-reperfusion (I/R) lesions and ventricular remodeling due to an acute myocardial infarction (AMI). Colchicine as a pleiotropic anti-inflammatory molecule may exert cardioprotective effects under acute ischemia. Here, we aimed to evaluate the impact of colchicine on reperfusion injury in a mouse model. METHOD Myocardial ischemia/reperfusion (I/R) injury was induced in C57BL/6 male mice, after 45min ligation of the left coronary artery followed by reperfusion. 400μg/kg of colchicine or the vehicle was administrated intraperitoneally (i.p.) 25min before the reperfusion (blinded administration). Mice were sacrificed at 24h after the acute myocardial ischemia (AMI) and the infarct size was determined. Circulating level of troponin and cytokines profile were assessed 4h after the AMI. An echocardiography was performed in a follow-up group mice, 48h and 8weeks after the AMI. RESULTS The infarct size was reduced in colchicine treated mice (39.8±3.5% versus 52.9±3.2%, p<0.05). Troponin was significantly lower in the colchicine treated mice (7015.7±1423.7pg/mL, n=5 vs 30,723.7±7959.9pg/mL in the placebo group, n=6; p<0.0001). Fibrosis was decreased in the Colchicine group (24.51±3.13% vs 11.38±2.46%, p=0.03). In the follow-up group mice (n=8), there were no differences between mice treated with placebo (n=9) and mice treated with colchicine (n=9) regarding to cardiac remodeling parameters but outflow approximated by the ITV was higher in the colchicine group. CONCLUSION In conclusion, colchicine allowed a significant reduction of infarct size in mice, improves hemodynamic parameters and decrease cardiac fibrosis.

Anti-inflammatory drugs as promising cardiovascular treatments.

ABSTRACT Introduction: Inflammation is a well-known powerful effector of atherosclerosis development. Cell infiltration induces inflammatory signal increasing plaque formation as well as its destabilization, leading to cardiovascular disease including myocardial infarction. During ischemia, necrotic cardiomyocytes stimulate the inflammatory storm into the myocardium (by chemokines, vascular adhesion molecules, interleukins action) promoting cardiac repair but also remodeling. Areas covered: Herein the authors present each condition (atherosclerosis and myocardial infarction) in two separate parts. Pathophysiology is briefly presented and focused on its implication in inflammation. Non-invasive techniques are presented, which explore inflammation in vivo. Several anti-inflammatory drugs are presented (mechanism of action, already published studies and ongoing trials are summarized). Expert commentary: Whereas atherosclerosis, regarding both the step-by-step pathophysiology and the acute plaque destabilization, is widely recognized as involving inflammatory pathways, the current translations in clinical practice remain poor. However, both basic and clinical research are active in the field, and the first large trials should soon be available, corroborating or not whether modulating inflammatory processes could be of interest in clinical practice.

Does ivabradine balance dobutamine effects in cardiogenic shock? A promising new strategy

Cardiogenic shock (CS) is associated with a high rate of in-hospital mortality and a poor prognosis. Inotropic agents, used in clinical practice, remain the cornerstone of the management of CS. Dobutamine is the most usually preferred in this indication. Despite its benefit effects, this drug also exerts adverse effects as sinus tachycardia, possibly deleterious in this context. In the recent ESC guidelines (Ponikowski et al. 2016), inotropic agents are clearly not recommended for the management of a patient with acute HF unless the patient is symptomatically hypotensive or hypoperfused because of safety concern (class III, A). Shortterm, intravenous infusion of inotropic agents may be considered in patients with hypotension (SBP < 90 mmHg) and/or signs of hypoperfusion (despite adequate volemia), in order to maintain and improve the cardiac outflow, peripheral perfusion and maintain end-organ function (class IIb, level C). Dobutamine has even been suggested to increase mortality (O’Connor et al. 1999, Wang et al. 2015). The level of recommendation and the years of publications of main trials in the field underline that we lack data, regarding both basic models and clinical trials. We lack strong clinical data in the field. Only few trials are currently studying CS (Table 1). As indicated in the Table 1, there are some epidemiological or prognostic evaluations, some trials on mechanical assistances and devices, but surprisingly few studies with drugs (and none evaluating ivabradine in this context to our knowledge). A few years ago, the interest of intra-aortic balloon support for patients with acute myocardial infarction leading to CS has been definitely challenged (Thiele et al. 2012, 2013), reinforcing the lack of trials and recommendations with strong level of evidence. Even epidemiological data are rather scarce and local uses are heterogeneous. Recently, a multi-centre study (Harjola et al. 2015) included in nine centres representing eight countries. A total of 219 patients were included over 2 years, underlining the high difficulties to conduct a trial in the field. Consistently, FRENCHSHOCK, a French nationwide registry, is currently ongoing (NCT02703038). Its aim is to reflect the current practice in the field, including the likely heterogeneous clinical strategies, in a nationwide registry, in the as short as possible framework (>500 patients in less than 6 months). Importantly, this registry aims to present real-life clinical features and management of more than 500 patients in various centres. The current management of CS is indeed crucial including the real use of inotropic drugs and their prognostic impact. We lack basic data in the field. In the study published in this journal, Bakkehaug et al. (2016) reported a basic model of CS (Bakkehaug et al. 2016). The aim of the authors was to evaluate the effect of a combined therapy by dobutamine and ivabradine in a model of post-ischaemic low cardiac output. Indeed, both inotropic impact and induced tachycardia by dobutamine participate to increase the cardiac output in CS. On the other hand, the induced sinus tachycardia could exert in turn deleterious effects (we could also cite other side effects such as arrhythmias). Indeed, increased tachycardia may increase left ventricular work inducing myocardial ischaemia and shortening diastole period and then efficient ventricular filling. Ivabradine is a specific blocker of the If funny current supported by the hyperpolarization-activated cyclic nucleotide-gated channels. This ionic current is involved in activity of the sinoatrial node. The interest of ivabradine is the reduction of heart rate without depressing myocardial inotropism or decreasing cardiac output (Roubille & Tardif 2013). This reduction remains mild (about 9 bpm in the clinical trials in patients with HF), which appears compatible with haemodynamics adaptation and not compromising this adaptive tentative, hence its theoretical interest in this setting (Roubille et al. 2013, Lattuca&Roubille 2015). Ivabradine is currently indicated in chronic heart failure (class IIa, level B), in patients in sinus rhythm with a left ventricular ejection fraction <35% and heart rate <70% despite treatment with an evidence-based dose of beta-blockers, angiotensin-converting enzyme inhibitor and a mineralo-corticoid receptor antagonist (Ponikowski et al. 2016). Importantly, it is currently not recommended in patients with acute HF as no randomized large trials addressed this issue. Only few data are available concerning its indication in CS.

Evaluation of the sST2-guided optimization of medical treatments of patients admitted for heart failure, to prevent readmission: Study protocol for a randomized controlled trial

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Evaluation of the sST2-guided optimization of medical treatments of patients admitted for heart failure, to prevent readmission: Study protocol for a randomized controlled trial Corentin Curinier, Kamila Solecki, Anne Dupuy, Cyril Breuker, Manuela Lotierzo, Laetitia Zerkowski, Eran Kalmanovich, Mariama Akodad, Jérôme Adda, Pascal Battistella, et al.

An hs-TNT Second Peak Associated with High CRP at Day 2 Appears as Potential Biomarkers of Micro-Vascular Occlusion on Magnetic Resonance Imaging after Reperfused ST-Segment Elevation Myocardial Infarction

Introduction: Micro-vascular occlusion (MVO) in a myocardial infarction (MI) is associated with an increased risk of heart failure and mortality. Hs-T-troponin has a double peak kinetic after MI. The aim was to determine if this kinetic was correlated to MVO evaluated by cardiac magnetic resonance imaging (MRI) after MI. Methods: This is a monocentric retrospective study. Inclusion criteria were hospitalization for MI, Thrombolysis In Myocardial Infarction flow 0 at coronary angiography, reperfusion within 12 h from the onset of chest pain, cardiac MRI within the first month, and a 5-days’ biological follow-up with at least hs-T-Troponin and C-reactive protein (CRP). Statistics were performed using the R software. Results: Ninety-eight patients were included. Fifty-three patients (54.1%) had MVO at MRI. The existence of MVO was associated with a trend of more kissing procedure during primary percutaneous coronary intervention (p = 0.06), a significantly more frequent second peak of troponin (p = 0.048), a significantly higher CRP level (p < 0.0001) and a longer time to balloon (p = 0.01). The association of CRP level above 40 mg/L at day 2 and the observation of a second peak of troponin were associated to 95% of MVO in ST-segment elevation MI patients. By contrast, in the absence of these 2 criteria, MVO was absent in 78% of the cases. This score was associated with a higher rate of hospitalisation at 2 years. Conclusion: A biological score integrating hs-TNT second peak and CRP might help to predict MVO and predict outcomes after reperfused MI in our population.

Is hypertriglyceridemia atherogenic

ASCVD reduction is based on LDL reduction, especially by statins. Highly elevated TG could be harmful, especially because of the risk of pancreatitis. Elevation of TG is mainly due to metabolic disorders and diabetes, alcohol intake and overweight. Genetic factors have been clearly identified in the most severe cases. TG have been generally considered as bystanders for cardiovascular diseases (CVD). Both biological and basic research provide strong data suggesting that TG-rich lipoproteins could be involved in the pathophysiology of CVD. Recent epidemiological and genetics studies strongly corroborate the causal role of TG in CVD. This paves the way for new approaches in the management of patients both for primary and secondary prevention.

Management of advanced heart failure: a review

ABSTRACT Introduction: Heart failure (HF) has become a global pandemic. Despite recent developments in both medical and device treatments, HF incidences continues to increase. The current definition of HF restricts itself to stages at which clinical symptoms are apparent. In advanced heart failure (AdHF), it is universally accepted that all patients are refractory to traditional therapies. As the number of HF patients increase, so does the need for additional treatments, with an increased proportion of patients requiring advanced therapies. Areas covered: This review discusses extensive evidence for the effect of medical treatment on HF, although the data on the effect on AdHF is scare. Authors review the relevant literature for treating AdHF patients. Furthermore, mechanical circulatory devices (MCD) have emerged as an alternative to heart transplantation and have been shown to enhance quality of life and reduce mortality therefore authors also review the current literature on the different MCD and technologies. Expert commentary: More patients will need advanced therapies, as the access to heart transplantation is limited by the number of available donors. AdHF patients should be identified timely since the window of opportunities for advanced therapy is narrow as their morbidity is progressive and survival is often short.

Management of acute heart failure: Contribution of daily bedside echocardiographic assessment on therapy adjustment with impact measure on the 30-day readmission rate (JECICA)

There are currently one million heart failure (HF) patients in France and the rate is progressively increases due to population aging. Acute decompensation of HF is the leading cause of hospitalization in people over 65 years of age with a 25% re-hospitalization rate in the first month. Expenses related to the management of HF in France in 2013 amounted to more than one billion euros, of which 65% were for hospitalizations alone. The management of acute decompensation is a challenge, due to the complexity of clinical and laboratory evaluation leading to therapeutic errors, which in turn leads to longer hospitalization, high early re-hospitalization and complications. Therapeutic adjustment, especially diuretic, in the acute phase (during hospitalization) affects early re-hospitalization rates (within 30 days). These adjustments can be based on clinical estimation and laboratory parameters, but echocardiography has been shown to be superior in estimating filling pressures (FP) compared to clinical and laboratory parameters. We hypothesize that a simple daily bedside echocardiographic assessment could provide a reproducible estimation of FP with an evaluation of mitral inflow and the inferior vena cava (IVC). This could allow a more reliable estimate of the true blood volume of the patient and thus lead to a more suitable therapeutic adjustment. This in turn should lead to a decrease in early re-admission rate (primary endpoint) and potentially decrease six-month mortality and rate of complications.

Letter to the editor concerning “comparative prognostic value of postprocedural creatine kinase myocardial band and high‐sensitivity troponin T in patients with non‐ST‐segment elevation myocardial infarction undergoing percutaneous coronary intervention”

Dear Editor, We read with interest the article entitled: Comparative prognostic value of postprocedural creatine kinase myocardial band and high-sensitivity troponin T in patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.” The authors aimed at assessing the prognostic value of two different biomarkers: creatine kinase myocardial band (CK-MB) and cardiac high-sensitivity troponin T (hs-TnT) after percutaneous coronary intervention (PCI) in patients admitted for non-ST-segment elevation myocardial infarction (NSTEMI). This study, including 2,077 patients, deals with a hot topic in interventional cardiology concerning risk stratification using biomarkers in patients undergoing PCI. The authors concluded that both CK-MB and hs-Tn T peaks were independent predictors of 3-years mortality in patients with NSTEMI undergoing PCI with a moderate strength of association and without significant difference between the biomarkers in head-to-head comparisons. This kind of study is highly relevant since very little is known specifically on many aspects of hs-troponins biomarkers. More often, the data obtained with standard troponins or CK have been considered equally reliable than that obtained with hs-troponins but this is still to be confirmed. Nevertheless, hs-troponins are mentioned as good biomarker for prognostic value after interventional cardiology and in clinical research, in relation to the ability to reflect infarct size and the correlation with no-reflow These findings concerning prognostic value of troponin were consistent with the literature [1]. The authors also stated that the threshold of biomarker elevation was different between both biomarkers, much more elevated for hs-TnT (>70 ULN cut-off) than for CK-MB (>3 times the ULN cut-off) as expected from a high-sensitive biomarker. However, as discussed by the authors, hs-TnT may be oversensitive in detecting periprocedural myocardial damage and a postprocedural hs-cTn elevation must be carefully interpreted [2]. There is still little knowledge on the ideal timing for assessing myocardial damage: early, the day after or even few days after. High-sensitivity biomarkers are sometimes misleading in clinical practice, and to our opinion, the clinicians have to be aware of advantages but also of pitfalls associated with these biomarkers. Consistently, we demonstrated a biphasic pattern of hs-TnT elevation in reperfused patients with acute myocardial infarction. Indeed, the biphasic pattern of hs-TnT elevation with an early (at a median of 11.8 hr from admission) high amplitude peak and a late peak of lower amplitude occurring 3–4 days thereafter has been described in a recent article [3]. These findings were consistent with the previously published study of Solecki et al. with an early peak at 12 hr for hs-TnT and a second peak at 82 hr [4]. This aspect is tricky in clinical practice and has not been addressed in this study. Moreover, patients included in this studywere admitted for NSTEMI and biomarker elevation due to PCI procedure remains unclear. Thus, these findings cannot be applied for patients undergoing planned PCI. Last but not least, CK seems to be a great value venerable biomarker providing similar information to that of a more recent and fashioned one. In conclusion, this study highlighted the prognostic value of both CKMB and hs-TnT in patients admitted for NSTEMI undergoing PCI. These biomarkers may be complementary and should be assessed routinely for risk stratification. Their respective interest, the ideal timing, relationship with biomarkers including inflammatory or fibrosis biomarkers, as well as specific pathophysiological meaning remain to be investigated.

Potential Uses of Sacubitril/Valsartan: Need for Data on Efficacy and Safety

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been the cornerstone for the treatment of heart failure (HF) with reduced ejection fraction for decades. According to recent and promising studies, sacubitril/valsartan (SV) might be efficient in alternative indications in the area of HF with preserved left ventricular ejection fraction, chronic kidney disease, and so on. This review briefly summarizes these promising therapeutic options regarding SV and the potential limits and pitfalls for its use in routine practice (due to cognitive uncertainties).