The purpose of this study was to investigate the effect of empagliflozin on diastolic function in a nondiabetic heart failure with reduced ejection fraction (HFrEF) scenario and on the pathways ...causing diastolic dysfunction.
This group demonstrated that empagliflozin ameliorates adverse cardiac remodeling, enhances myocardial energetics, and improves left ventricular systolic function in a nondiabetic porcine model of HF. Whether empagliflozin also improves diastolic function remains unknown. Hypothetically, empagliflozin would improve diastolic function in HF mediated both by a reduction in interstitial myocardial fibrosis and an improvement in cardiomyocyte stiffness (titin phosphorylation).
HF was induced in nondiabetic pigs by 2-h balloon occlusion of proximal left anterior descending artery. Animals were randomized to empagliflozin or placebo for 2 months. Cardiac function was evaluated with cardiac magnetic resonance (CMR), 3-dimensional echocardiography, and invasive hemodynamics. In vitro relaxation of cardiomyocytes was studied in primary culture. Myocardial samples were obtained for histological and molecular evaluation. Myocardial metabolite consumption was analyzed by simultaneous blood sampling from coronary artery and coronary sinus.
Despite similar initial ischemic myocardial injury, the empagliflozin group showed significantly improved diastolic function at 2 months, assessed by conventional echocardiography (higher e′ and color M-mode propagation velocity, lower E/e′ ratio, myocardial performance Tei index, isovolumic relaxation time, and left atrial size), echocardiography-derived strain imaging (strain imaging diastolic index, strain rate at isovolumic relaxation time and during early diastole, and untwisting), and CMR (higher peak filling rate, larger first filling volume). Invasive hemodynamics confirmed improved diastolic function with empagliflozin (better peak LV pressure rate of decay (–dP/dt), shorter Tau, lower end-diastolic pressure-volume relationship (EDPVR), and reduced filling pressures). Empagliflozin reduced interstitial myocardial fibrosis at the imaging, histological and molecular level. Empagliflozin improved nitric oxide signaling (endothelial nitric oxide synthetase eNOS activity, nitric oxide NO availability, cyclic guanosine monophosphate (cGMP) content, protein kinase G PKG signaling) and enhanced titin phosphorylation (which is responsible for cardiomyocyte stiffness). Indeed, isolated cardiomyocytes exhibited better relaxation in empagliflozin-treated animals. Myocardial consumption of glucose and ketone bodies negatively and positively correlated with diastolic function, respectively.
Empagliflozin ameliorates diastolic function in a nondiabetic HF porcine model, mitigates histological and molecular remodeling, and reduces both left ventricle and cardiomyocyte stiffness.
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Diabetic nephropathy (DN) is the most common cause of end-stage renal disease and identification of new therapeutic targets is needed. Nicotinamide phosphoribosyltransferase (NAMPT) is both an ...extracellular and intracellular protein. Circulating NAMPT is increased in diabetics and in chronic kidney disease patients. The role of NAMPT in renal cell biology is poorly understood. NAMPT mRNA and protein were increased in the kidneys of rats with streptozotocin-induced diabetes. Immunohistochemistry localized NAMPT to glomerular and tubular cells in diabetic rats. The inflammatory cytokine TNFα increased NAMPT mRNA, protein and NAD production in cultured kidney human tubular cells. Exogenous NAMPT increased the mRNA expression of chemokines MCP-1 and RANTES. The NAMPT enzymatic activity inhibitor FK866 prevented these effects. By contrast, FK866 boosted TNFα-induced expression of MCP-1 and RANTES mRNA and endogenous NAMPT targeting by siRNA also had a proinflammatory effect. Furthermore, FK866 promoted tubular cell apoptosis in an inflammatory milieu containing the cytokines TNFα/IFNγ. In an inflammatory environment FK866 promoted tubular cell expression of the lethal cytokine TRAIL. These data are consistent with a role of endogenous NAMPT activity as an adaptive, protective response to an inflammatory milieu that differs from the proinflammatory activity of exogenous NAMPT. Thus, disruption of endogenous NAMPT function in stressed cells promotes tubular cell death and chemokine expression. This information may be relevant for the design of novel therapeutic strategies in DN.
•NAMPT is upregulated by inflammatory mediators in human tubular cells.•NAMPT as a potential therapeutic target in kidney injury•The role of endogenous NAMPT should be considered when studying NAMPT as a therapeutic target.
Pathophysiology of Acute Coronary Syndrome Santos-Gallego, Carlos G.; Picatoste, Belen; Badimón, Juan José
Current atherosclerosis reports,
04/2014, Letnik:
16, Številka:
4
Journal Article
Recenzirano
Despite improvements in interventional and pharmacological therapy for atherosclerotic disease, it is still the leading cause of death in the developed world. Hence, there is a need for further ...development of more effective therapeutic approaches. This requires better understanding of the molecular mechanisms and pathophysiology of the disease. Recent research in the last decade has changed our view of acute coronary syndrome (ACS): from a mere lipid deposition to an inflammatory disease; from ACS exclusively due to plaque rupture to the novel definitions of plaque erosion or calcified nodule; from the notion of a superimposed thrombus with necessary lethal consequences to the concept of healed plaques and thrombus contributing to plaque progression. In the hope of improving our understanding of ACS, all these recently discovered concepts are reviewed in this article.
Given that EMPA causes mild, persistent hyperketonemia, we hypothesized that cardiac benefits of EMPA are due to a shift in myocardial fuel metabolism away from glucose oxidation (energy inefficient) ...toward the energy-efficient fuel ketone bodies, which ameliorates cardiac remodeling Methods MI was induced in 16 pigs by 2-h balloon occlusion of proximal LAD. Pigs underwent cardiac MRI and 3D-echo (1 day and 2 month post-MI) as well as simultaneous sampling from LAD and coronary sinus (to measure myocardial metabolite consumption) Results Despite similar initial MI size in both groups (42±3% vs 42±2%, p=NS), EMPA ameliorated adverse cardiac remodeling at 2 month (Table) and reduced LV mass, volumes and sphericity, as well as neurohormonal activation (BNP and catecholamine).
The purpose of this study was to investigate the effect of empagliflozin on diastolic function in a nondiabetic heart failure with reduced ejection fraction (HFrEF) scenario and on the pathways ...causing diastolic dysfunction.
This group demonstrated that empagliflozin ameliorates adverse cardiac remodeling, enhances myocardial energetics, and improves left ventricular systolic function in a nondiabetic porcine model of HF. Whether empagliflozin also improves diastolic function remains unknown. Hypothetically, empagliflozin would improve diastolic function in HF mediated both by a reduction in interstitial myocardial fibrosis and an improvement in cardiomyocyte stiffness (titin phosphorylation).
HF was induced in nondiabetic pigs by 2-h balloon occlusion of proximal left anterior descending artery. Animals were randomized to empagliflozin or placebo for 2 months. Cardiac function was evaluated with cardiac magnetic resonance (CMR), 3-dimensional echocardiography, and invasive hemodynamics. In vitro relaxation of cardiomyocytes was studied in primary culture. Myocardial samples were obtained for histological and molecular evaluation. Myocardial metabolite consumption was analyzed by simultaneous blood sampling from coronary artery and coronary sinus.
Despite similar initial ischemic myocardial injury, the empagliflozin group showed significantly improved diastolic function at 2 months, assessed by conventional echocardiography (higher e' and color M-mode propagation velocity, lower E/e' ratio, myocardial performance Tei index, isovolumic relaxation time, and left atrial size), echocardiography-derived strain imaging (strain imaging diastolic index, strain rate at isovolumic relaxation time and during early diastole, and untwisting), and CMR (higher peak filling rate, larger first filling volume). Invasive hemodynamics confirmed improved diastolic function with empagliflozin (better peak LV pressure rate of decay (-dP/dt), shorter Tau, lower end-diastolic pressure-volume relationship (EDPVR), and reduced filling pressures). Empagliflozin reduced interstitial myocardial fibrosis at the imaging, histological and molecular level. Empagliflozin improved nitric oxide signaling (endothelial nitric oxide synthetase eNOS activity, nitric oxide NO availability, cyclic guanosine monophosphate (cGMP) content, protein kinase G PKG signaling) and enhanced titin phosphorylation (which is responsible for cardiomyocyte stiffness). Indeed, isolated cardiomyocytes exhibited better relaxation in empagliflozin-treated animals. Myocardial consumption of glucose and ketone bodies negatively and positively correlated with diastolic function, respectively.
Empagliflozin ameliorates diastolic function in a nondiabetic HF porcine model, mitigates histological and molecular remodeling, and reduces both left ventricle and cardiomyocyte stiffness.
Fingolimod, a sphingosine-1-phosphate receptor agonist, is used for the treatment of multiple sclerosis and exerts antiapoptotic properties. We hypothesized that sphingosine-1-phosphate receptor ...activation with fingolimod during acute myocardial infarction (MI) inhibits apoptosis, leading to increased myocardial salvage, reduced infarct size, and mitigated left ventricular (LV) remodeling in a porcine model of ischemia/reperfusion.
Ischemia/reperfusion was induced in pigs by balloon occlusion of the left anterior descending artery, followed by reperfusion. Animals randomly received fingolimod or saline (control). In short-term experiments, fingolimod treatment activated the cardioprotective reperfusion injury salvage kinase and survivor activating factor enhancement pathways in the infarct border zone 24 hours after MI, leading to decreased cardiomyocyte apoptosis and reduced myocardial oxidative stress. These effects were abolished by specific inhibitors of both pathways, demonstrating that fingolimod-induced cardioprotection was mediated by reperfusion injury salvage kinase and survivor activating factor enhancement pathways. In long-term experiments, fingolimod significantly improved myocardial salvage, reduced infarct size, and improved systolic LV function measured by cardiac magnetic resonance 1 week and 1 month after MI. Importantly, fingolimod mitigated the development of adverse post-MI LV remodeling 1 month after MI. Specifically, fingolimod treatment led to a significant reduction in LV mass, LV dilatation, and neurohormonal activation, and it preserved LV geometry. Furthermore, fingolimod decreased interstitial fibrosis, cardiomyocyte hypertrophy, and chronic activation of Akt and extracellular receptor kinase 1/2 in the remote noninfarcted myocardium.
Sphingosine-1-phosphate receptor activation with fingolimod during acute MI reduced infarct size via the reperfusion injury salvage kinase and survivor activating factor enhancement pathways, improved systolic LV function, and mitigated post-MI LV remodeling. Our data strongly support a cardioprotective role for sphingosine-1-phosphate receptor activation during MI.
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