The IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT): multicenter pig study on the effect of ischemic preconditioning.

Numerous cardioprotective interventions have been reported to reduce myocardial infarct size (IS) in pre-clinical studies. However, their translation for the benefit of patients with acute myocardial infarction (AMI) has been largely disappointing. One reason for the lack of translation is the lack of rigor and reproducibility in pre-clinical studies.

Efficacy of a cysteine protease inhibitor compared with enalapril in murine heart failure models.

Cysteine proteases calpains contribute to heart failure (HF), but it remains unknown whether their inhibition provides any benefit compared to standard pharmacological treatment for HF. Here, we characterize the pharmacological properties of NPO-2270 (NPO) as a potent inhibitor of cysteine proteases. Then, we describe that acute administration of NPO in rodent models of transient ischemia at the time of reperfusion reduces myocardial infarction, while its chronic oral administration attenuates adverse remodeling and cardiac dysfunction induced by ischemic and non-ischemic pathological stimuli more effectively than enalapril when given at the same dose.

Connexin 43 modulates reverse electron transfer in cardiac mitochondria from inducible knock-out Cx43 mice by altering the coenzyme Q pool.

Succinate accumulates during myocardial ischemia and is rapidly oxidized during reperfusion, leading to reactive oxygen species (ROS) production through reverse electron transfer (RET) from mitochondrial complex II to complex I, and favoring cell death. Given that connexin 43 (Cx43) modulates mitochondrial ROS production, we investigated whether Cx43 influences RET using inducible knock-out Cx43 mice. Oxygen consumption, ROS production, membrane potential and coenzyme Q (CoQ) pool were analyzed in subsarcolemmal (SSM, expressing Cx43) and interfibrillar (IFM) cardiac mitochondria isolated from wild-type Cx43 mice and Cx43 knock-out animals treated with 4-hydroxytamoxifen (4OHT).

Long-Term Protective Effects of Succinate Dehydrogenase Inhibition during Reperfusion with Malonate on Post-Infarction Left Ventricular Scar and Remodeling in Mice.

Succinate dehydrogenase inhibition with malonate during initial reperfusion reduces myocardial infarct size in both isolated mouse hearts subjected to global ischemia and in in situ pig hearts subjected to transient coronary ligature. However, the long-term effects of acute malonate treatment are unknown. Here, we investigated whether the protective effects of succinate dehydrogenase inhibition extend to a reduction in scar size and adverse left ventricular remodeling 28 days after myocardial infarction.

TRPV4 Channels Promote Pathological, but Not Physiological, Cardiac Remodeling through the Activation of Calcineurin/NFAT and TRPC6.

TRPV4 channels, which respond to mechanical activation by permeating Ca into the cell, may play a pivotal role in cardiac remodeling during cardiac overload. Our study aimed to investigate TRPV4 involvement in pathological and physiological remodeling through Ca-dependent signaling. TRPV4 expression was assessed in heart failure (HF) models, induced by isoproterenol infusion or transverse aortic constriction, and in exercise-induced adaptive remodeling models.

Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction.

Background And Aims: The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD.

Lysyl oxidase-dependent extracellular matrix crosslinking modulates calcification in atherosclerosis and aortic valve disease.

Extracellular matrix (ECM) is an active player in cardiovascular calcification (CVC), a major public health issue with an unmet need for effective therapies. Lysyl oxidase (LOX) conditions ECM biomechanical properties; thus, we hypothesized that LOX might impact on mineral deposition in calcific aortic valve disease (CAVD) and atherosclerosis. LOX was upregulated in calcified valves from two cohorts of CAVD patients.

Spontaneous reperfusion enhances succinate concentration in peripheral blood from stemi patients but its levels does not correlate with myocardial infarct size or area at risk.

Succinate is enhanced during initial reperfusion in blood from the coronary sinus in ST-segment elevation myocardial infarction (STEMI) patients and in pigs submitted to transient coronary occlusion. Succinate levels might have a prognostic value, as they may correlate with edema volume or myocardial infarct size. However, blood from the coronary sinus is not routinely obtained in the CathLab.

[Environment and cardiovascular health: causes, consequences and opportunities in prevention and treatment].

The environment is a strong determinant of cardiovascular health. Environmental cardiology studies the contribution of environmental exposures with the aim of minimizing the harmful influences of pollution and promoting cardiovascular health through specific preventive or therapeutic strategies. The present review focuses on particulate matter and metals, which are the pollutants with the strongest level of scientific evidence, and includes possible interventions.

Caged-carvedilol as a new tool for visible-light photopharmacology of β-adrenoceptors in native tissues.

Adrenoceptors are G protein-coupled receptors involved in a large variety of physiological processes, also under pathological conditions. This is due in large part to their ubiquitous expression in the body exerting numerous essential functions. Therefore, the possibility to control their activity with high spatial and temporal precision would constitute a valuable research tool.

Environment and cardiovascular health: causes, consequences and opportunities in prevention and treatment.

The environment is a strong determinant of cardiovascular health. Environmental cardiology studies the contribution of environmental exposures with the aim of minimizing the harmful influences of pollution and promoting cardiovascular health through specific preventive or therapeutic strategies. The present review focuses on particulate matter and metals, which are the pollutants with the strongest level of scientific evidence, and includes possible interventions.

Defective dimerization of FoF1-ATP synthase secondary to glycation favors mitochondrial energy deficiency in cardiomyocytes during aging.

Aged cardiomyocytes develop a mismatch between energy demand and supply, the severity of which determines the onset of heart failure, and become prone to undergo cell death. The FoF1-ATP synthase is the molecular machine that provides >90% of the ATP consumed by healthy cardiomyocytes and is proposed to form the mitochondrial permeability transition pore (mPTP), an energy-dissipating channel involved in cell death. We investigated whether aging alters FoF1-ATP synthase self-assembly, a fundamental biological process involved in mitochondrial cristae morphology and energy efficiency, and the functional consequences this may have.

Human Lysyl Oxidase Over-Expression Enhances Baseline Cardiac Oxidative Stress but Does Not Aggravate ROS Generation or Infarct Size Following Myocardial Ischemia-Reperfusion.

Lysyl oxidase (LOX) is an enzyme critically involved in collagen maturation, whose activity releases HO as a by-product. Previous studies demonstrated that LOX over-expression enhances reactive oxygen species (ROS) production and exacerbates cardiac remodeling induced by pressure overload. However, whether LOX influences acute myocardial infarction and post-infarct left ventricular remodeling and the contribution of LOX to myocardial oxidative stress following ischemia-reperfusion have not been analyzed.

Aging Impairs Reverse Remodeling and Recovery of Ventricular Function after Isoproterenol-Induced Cardiomyopathy.

Information about heart failure with reduced ejection fraction (HFrEF) in women and the potential effects of aging in the female heart is scarce. We investigated the vulnerability to develop HFrEF in female elderly mice compared to young animals, as well as potential differences in reverse remodeling. First, HF was induced by isoproterenol infusion (30 mg/kg/day, 28 days) in young (10-week-old) and elderly (22-month-old) female mice.

NR4A3: A Key Nuclear Receptor in Vascular Biology, Cardiovascular Remodeling, and Beyond.

The mechanisms committed in the activation and response of vascular and inflammatory immune cells play a major role in tissue remodeling in cardiovascular diseases (CVDs) such as atherosclerosis, pulmonary arterial hypertension, and abdominal aortic aneurysm. Cardiovascular remodeling entails interrelated cellular processes (proliferation, survival/apoptosis, inflammation, extracellular matrix (ECM) synthesis/degradation, redox homeostasis, etc.) coordinately regulated by a reduced number of transcription factors.

Implications of Iron Deficiency in STEMI Patients and in a Murine Model of Myocardial Infarction.

In patients with a first anterior ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention, iron deficiency (ID) was associated with larger infarcts, more extensive microvascular obstruction, and higher frequency of adverse left ventricular remodeling as assessed by cardiac magnetic resonance imaging. In mice, an ID diet reduced the activity of the endothelial nitric oxide synthase/soluble guanylate cyclase/protein kinase G pathway in association with oxidative/nitrosative stress and increased infarct size after transient coronary occlusion. Iron supplementation or administration of an sGC activator before ischemia prevented the effects of the ID diet in mice.

Citric Acid Cycle Metabolites Predict Infarct Size in Submitted to Transient Coronary Artery Occlusion and Treated with Succinate Dehydrogenase Inhibitors or Remote Ischemic Perconditioning.

Succinate dehydrogenase (SDH) inhibition with malonate during reperfusion reduced myocardial infarction in animals, whereas its endogenous substrate, succinate, is detected in plasma from STEMI patients. We investigated whether protection by SDH inhibition is additive to that of remote ischemic perconditioning (RIC) in submitted to transient coronary artery occlusion, and whether protective maneuvers influence plasma levels of citric acid cycle metabolites. Forty were submitted to 40 min coronary occlusion and reperfusion, and allocated to four groups (controls, sodium malonate 10 mmol/L, RIC, and malonate + RIC).

Connexins in the Heart: Regulation, Function and Involvement in Cardiac Disease.

Connexins are a family of transmembrane proteins that play a key role in cardiac physiology. Gap junctional channels put into contact the cytoplasms of connected cardiomyocytes, allowing the existence of electrical coupling. However, in addition to this fundamental role, connexins are also involved in cardiomyocyte death and survival.

Cellular crosstalk in cardioprotection: Where and when do reactive oxygen species play a role?

A well-balanced intercellular communication between the different cells within the heart is vital for the maintenance of cardiac homeostasis and function. Despite remarkable advances on disease management and treatment, acute myocardial infarction remains the major cause of morbidity and mortality worldwide. Gold standard reperfusion strategies, namely primary percutaneous coronary intervention, are crucial to preserve heart function.

Effect of COMBinAtion therapy with remote ischemic conditioning and exenatide on the Myocardial Infarct size: a two-by-two factorial randomized trial (COMBAT-MI).

Remote ischemic conditioning (RIC) and the GLP-1 analog exenatide activate different cardioprotective pathways and may have additive effects on infarct size (IS). Here, we aimed to assess the efficacy of RIC as compared with sham procedure, and of exenatide, as compared with placebo, and the interaction between both, to reduce IS in humans. We designed a two-by-two factorial, randomized controlled, blinded, multicenter, clinical trial.

H NMR serum metabolomic profiling of patients at risk of cardiovascular diseases performing stress test.

Cardiovascular diseases are the leading cause of death worldwide. Changes in lifestyle and/or pharmacological treatment are able to reduce the burden of coronary artery diseases (CAD) and early diagnosis is crucial for the timely and optimal management of the disease. Stress testing is a good method to measure the burden of CAD but it is time consuming and pharmacological testing may not fully mimic exercise test.

Connexin 43 Deficiency Is Associated with Reduced Myocardial Scar Size and Attenuated TGFβ1 Signaling after Transient Coronary Occlusion in Conditional Knock-Out Mice.

Previous studies demonstrated a reduction in myocardial scar size in heterozygous Cx43 mice subjected to permanent coronary occlusion. However, patients presenting with ST segment elevation myocardial infarction often undergo rapid coronary revascularization leading to prompt restoration of coronary flow. Therefore, we aimed to assess changes in scar size and left ventricular remodeling following transient myocardial ischemia (45 min) followed by 14 days of reperfusion using Cx43 (controls) and Cx43 inducible knock-out (Cx43 content: 50%) mice treated with vehicle or 4-hydroxytamoxifen (4-OHT) to induce a Cre-ER(T)-mediated global deletion of the Cx43 floxed allele.

CIBER-CLAP (CIBERCV Cardioprotection Large Animal Platform): A multicenter preclinical network for testing reproducibility in cardiovascular interventions.

Despite many cardioprotective interventions have shown to protect the heart against ischemia/reperfusion injury in the experimental setting, only few of them have succeeded in translating their findings into positive proof-of-concept clinical trials. Controversial and inconsistent experimental and clinical evidence supports the urgency of a disruptive paradigm shift for testing cardioprotective therapies. There is a need to evaluate experimental reproducibility before stepping into the clinical arena.