Background
The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is complex and multifactorial. Chronotropic incompetence (ChI) has emerged as a crucial pathophysiological ...mechanism. Beta‐blockers, drugs with negative chronotropic effects, are commonly used in HFpEF, although current evidence does not support its routine use in these patients.
Hypothesis
We postulate beta‐blockers may have deleterious effects in HFpEF and ChI. This work aims to evaluate the short‐term effect of beta‐blockers withdrawal on functional capacity assessed by the maximal oxygen uptake (peakVO2) in patients with HFpEF and ChI.
Methods
This is a prospective, crossover, randomized (1:1) and multicenter study. After randomization, the clinical and cardiac rhythm will be continuously registered for 30 days. PeakVO2 is assessed by cardiopulmonary exercise testing (CPET) at 15 and 30 days in both groups. Secondary endpoints include quality of life, cognitive, and safety assessment. Patients with stable HFpEF, functional class New York Heart Association (NYHA) II‐III, chronic treatment with beta‐blockers, and ChI will be enrolled. A sample size estimation alfa: 0.05, power: 90%, a 20% loss rate, and delta change of mean peakVO2: +1.2 mL/kg/min (SD ± 2.0) of 52 patients is necessary to test our hypothesis.
Results
Patients started enrolling in October 2018. As January 14th, 2020, 28 patients have been enrolled. It is projected to enroll the last patient at the end of July 2020.
Conclusions
Optimizing therapy that improves functional capacity remains an unmeet priority in HFpEF. Deprescribing beta‐blockers in patients with HFpEF and ChI seems a plausible intervention to improve functional capacity. This trial is an attempt towards precision medicine in this complex syndrome.
Trial registration
ClinicalTrials.gov: NCT03871803.
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The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial made evident the potentiality of pharmacological ...sodium-glucose cotransporter 2 (SGLT2) inhibition for treating patients with diabetes and cardiovascular disease. Since the effect of empagliflozin or other SGLT2 inhibitors on the whole cardiac metabolic profile was never analysed before, and with the purpose to contribute to elucidate the benefits at cardiac level of the use of empagliflozin, we explored the effect of the treatment with empagliflozin for six weeks on the cardiac metabolomic profile of Zucker diabetic fatty rats, a model of early stage T2DM, using untargeted metabolomics approach. Empagliflozin reduced significantly the cardiac content of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (major bioactive contributing factors linking insulin resistance to cardiac damage) and decreased the cardiac content of the fatty acid transporter cluster of differentiation 36 (CD36); induced significant decreases of the cardiac levels of essential glycolysis intermediaries 2,3-bisphosphoglycerate and phosphoenolpyruvate, and regulated the abundance of several amino acids of relevance as tricarboxylic acid suppliers and/or in the metabolic control of the cardiac function as glutamic acid, gamma-aminobutyric acid and sarcosine. Empagliflozin treatment activated the cardioprotective master regulator of cellular energyhomeostasis AMP-activatedproteinkinase (AMPK) and enhanced autophagy at cardiac level, while it decreased significantly the cardiac mRNA levels of the pro-inflammatory cytokines interleukin-6 (IL-6), chemerin, TNF-α and MCP-1, reinforcing the hypothesis of a direct role for empagliflozin in attenuating cardiac inflammation. Our results provide an advancement on the knowledge of the mechanisms linking the therapy with empagliflozin with protective effects on the development of cardiometabolic diseases whose course is associated with remarkable cardiac bioenergetics dysregulation and disarrangement in cardiac metabolome and lipidome.
Telemedicine (TM) is potentially a way of escalating heart failure (HF) multidisciplinary integrated care. Despite the initial efforts to implement TM in HF management, we are still at an early stage ...of its implementation. The coronavirus disease 2019 pandemic led to an increased utilisation of TM. This tendency will probably remain after the resolution of this threat. Face-to-face medical interventions are gradually transitioning to the virtual setting by using TM. TM can improve healthcare accessibility and overcome geographic inequalities. It promotes healthcare system efficiency gains, and improves patient self-management and empowerment. In cooperation with human intervention, artificial intelligence can enhance TM by helping to deal with the complexities of multicomorbidity management in HF, and will play a relevant role towards a personalised HF patient approach. Artificial intelligence-powered/telemedical/heart team/multidisciplinary integrated care may be the next step of HF management. In this review, the authors analyse TM trends in the management of HF patients and foresee its future challenges within the scope of HF multidisciplinary integrated care.
Aims
Rivaroxaban, a direct inhibitor of activated factor X (FXa), is the only new oral anticoagulant approved for secondary prevention after acute coronary syndrome. Our objective was to identify the ...possible molecular mechanisms of rivaroxaban that contribute to endothelial function.
Methods
Cell viability and growth of human umbilical vein endothelial cells (HUVEC) were registered. Gene expression studies comparing the effects of rivaroxaban and FXa were conducted by a selective RNA array and confirmed by protein quantification. Wound‐healing experiments on HUVEC, platelet adhesion, enzymatic activity, and cell‐based assays for fibrin formation were performed with rivaroxaban.
Results
Rivaroxaban (50 nM) only altered (>2 fold change) the expression of matrix metallopeptidase 2 and urokinase plasminogen activator (u‐PA), but counteracted the FXa (9 nM)‐induced upregulation of several pro‐inflammatory genes (P < 0.05) and FXa‐enhanced platelet adhesion over HUVEC. Rivaroxaban increased u‐PA protein expression in HUVEC supernatants and enhanced u‐PA activity (up to 4 IU ng−1 of u‐PA). Rivaroxaban (1 nM–1 μM) showed a significant and dose‐dependent positive effect on HUVEC growth that was inhibited by BC‐11‐hydroxibromide, an inhibitor of u‐PA. Healing properties after a wound on HUVEC cultures, and fibrinolytic properties were also shown by rivaroxaban. Both effects were reversed by BC‐11‐hydroxibromide.
Conclusions
Rivaroxaban enhanced viability, growth and migration of HUVEC, mainly by u‐PA activation and upregulation, which also participate in the rivaroxaban‐induced fibrinolytic activity at endothelial level. Rivaroxaban also protected from the pro‐inflammatory effects of FXa on HUVEC. Altogether may improve endothelial functionality and could contribute to the cardiovascular benefits of rivaroxaban.
Cardiovascular disease (CVD) is the leading cause of death in the world. In 2019, 550 million people were suffering from CVD and 18 million of them died as a result. Most of them had associated risk ...factors such as high fasting glucose, which caused 134 million deaths, and obesity, which accounted for 5.02 million deaths. Diabesity, a combination of type 2 diabetes and obesity, contributes to cardiac, metabolic, inflammation and neurohumoral changes that determine cardiac dysfunction (diabesity-related cardiomyopathy). Epicardial adipose tissue (EAT) is distributed around the myocardium, promoting myocardial inflammation and fibrosis, and is associated with an increased risk of heart failure, particularly with preserved systolic function, atrial fibrillation and coronary atherosclerosis. In fact, several hypoglycaemic drugs have demonstrated a volume reduction of EAT and effects on its metabolic and inflammation profile. However, it is necessary to improve knowledge of the diabesity pathophysiologic mechanisms involved in the development and progression of cardiovascular diseases for comprehensive patient management including drugs to optimize glucometabolic control. This review presents the mechanisms of diabesity associated with cardiovascular disease and their therapeutic implications.
The modulation of acetylcholine (ACh) release by botulinum toxin injection into epicardial fat diminishes atrial fibrillation (AF) recurrence. These results suggest an interaction between autonomic ...imbalance and epicardial fat as risk factors of AF. Our aim was to study the inflammatory, lipidic and fibroblastic profile of epicardial stroma from patients who underwent open‐heart surgery, their regulation by cholinergic activity and its association with AF. We performed in vitro and ex vivo assays from paired subcutaneous and epicardial stromal cells or explants from 33 patients. Acute ACh effects in inflammation and lipid‐related genes were analysed by qPCR, in intracellular calcium mobilization were performed by Fluo‐4 AM staining and in neutrophil migration by trans‐well assays. Chronic ACh effects on lipid accumulation were visualized by AdipoRed. Plasma protein regulation by parasympathetic denervation was studied in vagotomized rats. Our results showed a higher pro‐inflammatory profile in epicardial regarding subcutaneous stromal cells. Acute ACh treatment up‐regulated monocyte chemoattractant protein 1 levels. Chronic ACh treatment improved lipid accumulation within epicardial stromal cells (60.50% 22.82‐85.13 vs 13.85% 6.17‐23.16, P < .001). Additionally, patients with AF had higher levels of fatty acid‐binding protein 4 (1.54 ± 0.01 vs 1.47 ± 0.01, P = .005). Its plasma levels were pronouncedly declined in vagotomized rats (2.02 ± 0.21 ng/mL vs 0.65 ± 0.23 ng/mL, P < .001). Our findings support the characterization of acute or chronic cholinergic activity on epicardial stroma and its association with AF.
Association between obesity and cardiovascular diseases is well known, however increased susceptibility of obese patients to develop several cancer types is not so commonly known. Current data ...suggest that poorer overall survival in cancer patients might be associated to non-cancer-related causes such as higher risk of cardiotoxicity in obese patients treated with chemotherapeutic agents. Omentin, a novel adipokine decreased in obesity, is actually in the spotlight due to its favourable effects on inflammation, glucose homeostasis and cardiovascular diseases. Also, recent data showed that in vitro anthracycline-induced cardiomyocyte apoptosis is counteracted by omentin suggesting its cardioprotective role.
Our aim was to evaluate omentin effects against docetaxel toxicity.
Our data indicate that omentin inhibits docetaxel-induced viability loss and that increased viability is associated to decreased caspase-3 expression and cell death. Although omentin reduces NOX4 expression, it failed to reduce docetaxel-induced reactive oxygen species production. Our results indicate that omentin decreases docetaxel-induced endoplasmic reticulum stress, suggesting that cardioprotective role might be associated to ERS inhibition.
These data suggest that omentin treatment may contribute to decrease susceptibility to DTX-induced cardiotoxicity.
Objective
Epicardial adipose tissue (EAT) in coronary artery disease is insulin resistant and has a proinflammatory profile. This study examined the regulation of EAT by exogenous omentin and its ...consequence on vascular cells.
Methods
Stromal vascular cells (SC) of EAT and subcutaneous adipose tissue (SAT) from patients who underwent heart surgery were cultured and exposed to adipogenic factors with or without omentin. Proinflammatory cytokine regulation by omentin was analyzed in SC and mature adipocytes. Glucose uptake by EAT and SAT explants was determined after insulin, omentin, or combined treatment. Human vascular cells were exposed to secretomes of SC, with and without omentin treatment. Migration of smooth muscle cells and expression of adhesion molecules were determined by wound healing or real‐time polymerase chain reaction, respectively.
Results
Omentin treatment raised adipogenesis‐induced adiponectin levels on SC of EAT and reduced TNF‐α expression levels (0.58 ± 0.14‐fold change; P = 0.034) in mature adipocytes. Omentin improved the insulin activity of EAT and SAT explants from cardiovascular disease patients. Finally, secretomes of SC under omentin treatment reduced the migration of smooth muscle cells.
Conclusions
Exogenous omentin might support a cardioprotective role through its effect on EAT regarding glucose uptake, anti‐inflammatory response, and its paracrine role on smooth muscle cells.
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