Rapid Replenishment of Phylloquinone in the Plasma and Liver Using Hyaluronan-Based Nanocapsules Reverses Endothelial Dysfunction in Mice.

Introduction: As vitamin K (phylloquinone, PK) displays vasoprotective effect, low dietary intake and poor bioavailability of PK may result in insufficient systemic levels for maintaining vascular health. This study aimed to test whether PK in hyaluronan-based nanocapsules (PK-Oil-HyC12) improves PK pharmacokinetics and endothelial function compared to PK in oil emulsion (PK-Oil).

Methods: PK pharmacokinetics in plasma, liver and aorta were analysed after single, oral administration of PK (10 mg/kg) in oil (PK-Oil) or encapsulated in hyaluronan-based nanocapsules with oil core (PK-Oil-HyC12) in mice using liquid chromatography-tandem mass spectrometry with atmospheric pressure chemical ionization method.

Special focus on the mitochondria in endothelial cells: A novel therapeutic target for gliflozins?

Gliflozins, also known as sodium-glucose cotransporter 2 inhibitors (SGLT2i), constitute a new class of antidiabetic drugs shown to reduce cardiovascular mortality and decrease hospitalisation frequency in patients with heart failure (HF), regardless of coexisting type 2 diabetes. In addition to lowering blood glucose levels by inhibiting renal glucose reabsorption, SGLT2i also affects sodium transport and improves cardiomyocyte mitochondrial function and energy metabolism. The influence of gliflozins on the metabolism and function of endothelial cells is not well understood.

Dapagliflozin, An SGLT2 Inhibitor, Improves Endothelial Cell Energy Metabolism Through Enhanced Mitochondrial Respiration.

Background/aims: Flozins (sodium-glucose cotransporter 2 inhibitors, SGLT2i) are a new class of antidiabetic drugs that reduce cardiovascular mortality and hospitalization rates in heart failure, regardless of type 2 diabetes status. Besides lowering glycemia by inhibiting renal glucose reabsorption, SGLT2 inhibitors may exert sodium-dependent hemodynamic effects and improve cardiomyocyte energy metabolism, substrate preference, and mitochondrial function. However, their impact on endothelial cells remains largely unknown.

Cardiac Fibrosis: Mechanistic Discoveries Linked to SGLT2 Inhibitors.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is), commonly known as flozins, have garnered attention not only for their glucose-lowering effects in type 2 diabetes mellitus (T2DM) but also for their cardioprotective properties. This review examines the mechanisms underlying the anti-fibrotic effects of SGLT2is, with a focus on key clinical trials and preclinical models. SGLT2is, mainly empagliflozin and dapagliflozin, have demonstrated significant reductions in heart failure-related hospitalizations, cardiovascular death, and fibrosis markers, independent of their glucose-lowering effects.

IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT): a small animal acute myocardial infarction randomized-controlled multicenter study on the effect of ischemic preconditioning.

Although many cardioprotective interventions have been shown to limit infarct size (IS), in preclinical animal studies of acute myocardial ischemia/reperfusion injury (IRI), their clinical translation to patient benefit has been largely disappointing. A major factor is the lack of rigor and reproducibility in the preclinical studies. To address this, we have established the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) small animal multisite acute myocardial infarction (AMI) network, with centralized randomization and blinded core laboratory IS analysis, and have validated the network using ischemic preconditioning (IPC).

Epicardial fat density obtained with computed tomography imaging - more important than volume?

Epicardial adipose tissue (EAT) is a unique fat depot located between the myocardium and the visceral layer of pericardium. It can be further subdivided into pericoronary (PCAT), periatrial (PAAT) and periventricular adipose tissue (PVentAT), each of them exhibiting specific characteristics and association with the underlying tissue. Since no physical barrier separates EAT from the myocardium, this fat tissue can easily interact with the underlying cardiac structure.

Epicardial fat in heart failure-Friend, foe, or bystander.

Epicardial adipose tissue (EAT) is a fat depot covering the heart. No physical barrier separates EAT from the myocardium, so EAT can easily affect the underlying cardiac muscle. EAT can participate in the development and progression of heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF).

Myo-inositol trispyrophosphate prevents right ventricular failure and improves survival in monocrotaline-induced pulmonary hypertension in the rat.

Background And Purpose: Pulmonary hypertension (PH) results from pulmonary vasculopathy, initially leading to a compensatory right ventricular (RV) hypertrophy, and eventually to RV failure. Hypoxia can trigger both pulmonary vasculopathy and RV failure. Therefore, we tested if myo-inositol trispyrophosphate (ITPP), which facilitates oxygen dissociation from haemoglobin, can relieve pulmonary vasculopathy and RV hypoxia, and eventually prevent RV failure and mortality in the rat model of monocrotaline-induced PH.

Non-coding RNA therapeutics in the treatment of heart failure.

Non-coding RNA (ncRNA) therapeutics can target either ncRNAs or conventional messenger RNA, offering both superior pharmacokinetics and selectivity to conventional therapies and addressing new, previously unexplored pathways. Although no ncRNA has yet been approved for the treatment of heart failure, in this review we present five most promising pathways and agents that either are in human clinical trials or offer great promise in the near future.

Sex- and age-dependent susceptibility to ventricular arrhythmias in the rat heart ex vivo.

The incidence of life-threatening ventricular arrhythmias, the most common cause of sudden cardiac death (SCD), depends largely on the arrhythmic substrate that develops in the myocardium during the aging process. There is a large deficit of comparative studies on the development of this substrate in both sexes, with a particular paucity of studies in females. To identify the substrates of arrhythmia, fibrosis, cardiomyocyte hypertrophy, mitochondrial density, oxidative stress, antioxidant defense and intracellular Ca signaling in isolated cardiomyocytes were measured in the hearts of 3- and 24-month-old female and male rats.

Epicardial fat and ventricular arrhythmias.

The arrhythmogenic role of epicardial adipose tissue (EAT) in atrial arrhythmias is well established, but its effect on ventricular arrhythmias has been significantly less investigated. Since ventricular arrhythmias are thought to cause 75%-80% of cases of sudden cardiac death, this is not a trivial issue. We provide an overview of clinical data as well as experimental and molecular data linking EAT to ventricular arrhythmias, attempting to dissect possible mechanisms and indicate future directions of research and possible clinical implications.

Arginase Inhibition Mitigates Bortezomib-Exacerbated Cardiotoxicity in Multiple Myeloma.

Background: Multiple myeloma (MM) is associated with increased cardiovascular morbidity and mortality, while MM therapies also result in adverse cardiac effects. Endothelial dysfunction and impaired nitric oxide (NO) pathway is their possible mediator.

Objective: Since MM is associated with increased arginase expression, resulting in the consumption of ʟ-arginine, precursor for NO synthesis, our aim was to test if cardiotoxicity mediated by MM and MM therapeutic, bortezomib (a proteasome inhibitor), can be ameliorated by an arginase inhibitor through improved endothelial function.

Right Ventricle Remodelling in Left-Sided Heart Failure in Rats: The Role of Calcium Signalling.

Right ventricular dysfunction (RVD) can follow primary pulmonary diseases, but the most common cause of its development is left-sided heart failure (HF). RVD is associated with HF progression, increased risk of death and hospitalisation. The mechanism of right ventricle (RV) remodelling leading to RVD due to left-sided HF is not fully elucidated.

Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity.

Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice.

Ventricular arrhythmias in acute myocardial ischaemia-Focus on the ageing and sex.

Annually, approximately 17 million people die from cardiovascular diseases worldwide, half of them suddenly. The most common direct cause of sudden cardiac death is ventricular arrhythmia triggered by an acute coronary syndrome (ACS). The study summarizes the knowledge of the mechanisms of arrhythmia onset during ACS in humans and in animal models and factors that may influence the susceptibility to life-threatening arrhythmias during ACS with particular focus on the age and sex.

New potential treatment for cardiovascular disease through modulation of hemoglobin oxygen binding curve: Myo-inositol trispyrophosphate (ITPP), from cancer to cardiovascular disease.

The human body is a highly aerobic organism, which needs large amount of oxygen, especially in tissues characterized by high metabolic demand, such as the heart. Inadequate oxygen delivery underlies cardiovascular diseases, such as coronary artery disease, heart failure and pulmonary hypertension. Hemoglobin, the oxygen-transport metalloprotein in the red blood cells, gives the blood enormous oxygen carrying capacity; thus oxygen binding to hemoglobin in the lungs and oxygen dissociation in the target tissues are crucial points for oxygen delivery as well as potential targets for intervention.

Regulation of N6-Methyladenosine after Myocardial Infarction.

Development of heart failure (HF) after myocardial infarction (MI) is responsible for premature death. Complex cellular and molecular mechanisms are involved in this process. A number of studies have linked the epitranscriptomic RNA modification N6-methyladenosine (m6A) with HF, but it remains unknown how m6A affects the risk of developing HF after MI.

Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

Life-threatening ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation remain an ongoing clinical problem and their prevention and treatment require optimization. Conventional antiarrhythmic drugs are associated with significant proarrhythmic effects that often outweigh their benefits. Another option, the implantable cardioverter defibrillator, though clearly the primary therapy for patients at high risk of ventricular arrhythmias, is costly, invasive, and requires regular monitoring.

Right ventricular myocardial oxygen tension is reduced in monocrotaline-induced pulmonary hypertension in the rat and restored by myo-inositol trispyrophosphate.

Pulmonary hypertension (PH) initially results in compensatory right ventricular (RV) hypertrophy, but eventually in RV failure. This transition is poorly understood, but may be triggered by hypoxia. Measurements of RV oxygen tension (pO) in PH are lacking.

Effect of age and sex on the incidence of ventricular arrhythmia in a rat model of acute ischemia.

Background: The impact of sex and age on the arrhythmic susceptibility within the setting of acute ischemia is masked by the fact that acute coronary events result from coronary artery disease appearing with age much earlier among men than among women.

Methods And Results: LAD ligation or sham operations were performed in rats of both sexes at the age 3 and 24 months. An ECG was recorded continuously for 6 h after the operation.

Systemic iron deficiency does not affect the cardiac iron content and progression of heart failure.

Chronic heart failure (HF) is often accompanied by systemic iron deficiency (ID). However, effects of ID on cardiac iron status and progression of HF are unknown. To investigate these effects rats underwent LAD ligation to induce post-myocardial infarction HF or sham operation.

Effect of ivabradine on cardiac arrhythmias: Antiarrhythmic or proarrhythmic?

Cardiac arrhythmias are a major source of mortality and morbidity. Unfortunately, their treatment remains suboptimal. Major classes of antiarrhythmic drugs pose a significant risk of proarrhythmia, and their side effects often outweigh their benefits.

Ivabradine prevents deleterious effects of dopamine therapy in heart failure: No role for HCN4 overexpression.

Background: Exacerbations of chronic heart failure (CHF) are often treated with catecholamines to provide short term inotropic support, but this strategy is associated with long-term detrimental hemodynamic effects and increased ventricular arrhythmias (VA), possibly related to increased heart rate (HR). We hypothesized that ivabradine may prevent adverse effects of short-term dopamine treatment in CHF.

Methods: Rats with post-myocardial infarction CHF received 2-week infusion of saline, dopamine(D), ivabradine(I) or D&I; cardiac function was assessed using echocardiography and pressure-volume loops while VA were assessed using telemetric ECG recording.