Reduced levels of creatine and total adenine nucleotides (sum of ATP, ADP and AMP) are hallmarks of chronic heart failure and restoring these pools is predicted to be beneficial by maintaining the ...diseased heart in a more favourable energy state. Ribose supplementation is thought to support both salvage and re-synthesis of adenine nucleotides by bypassing the rate-limiting step. We therefore tested whether ribose would be beneficial in chronic heart failure in control mice and in mice with elevated myocardial creatine due to overexpression of the creatine transporter (CrT-OE).
FOUR GROUPS WERE STUDIED: sham; myocardial infarction (MI); MI+ribose; MI+CrT-OE+ribose. In a pilot study, ribose given in drinking water was bioavailable, resulting in a two-fold increase in myocardial ribose-5-phosphate levels. However, 8 weeks post-surgery, total adenine nucleotide (TAN) pool was decreased to a similar amount (8-14%) in all infarcted groups irrespective of the treatment received. All infarcted groups also presented with a similar and substantial degree of left ventricular (LV) dysfunction (3-fold reduction in ejection fraction) and LV hypertrophy (32-47% increased mass). Ejection fraction closely correlated with infarct size independently of treatment (r(2) = 0.63, p<0.0001), but did not correlate with myocardial creatine or TAN levels.
Elevating myocardial ribose and creatine levels failed to maintain TAN pool or improve post-infarction LV remodeling and function. This suggests that ribose is not rate-limiting for purine nucleotide biosynthesis in the chronically failing mouse heart and that alternative strategies to preserve TAN pool should be investigated.
Mitochondria-targeted H
S donors are thought to protect against acute ischemia-reperfusion (IR) injury by releasing H
S that decreases oxidative damage. However, the rate of H
S release by current ...donors is too slow to be effective upon administration following reperfusion. To overcome this limitation here we develop a mitochondria-targeted agent, MitoPerSulf that very rapidly releases H
S within mitochondria. MitoPerSulf is quickly taken up by mitochondria, where it reacts with endogenous thiols to generate a persulfide intermediate that releases H
S. MitoPerSulf is acutely protective against cardiac IR injury in mice, due to the acute generation of H
S that inhibits respiration at cytochrome c oxidase thereby preventing mitochondrial superoxide production by lowering the membrane potential. Mitochondria-targeted agents that rapidly generate H
S are a new class of therapy for the acute treatment of IR injury.
Aims
The aim of this scoping review is to evaluate the current biomarkers used in the assessment of adverse cardiac remodelling in people with diabetes mellitus (DM) and in the diagnosis and ...prognosis of subsequent cardiovascular disease. We aim to discuss the biomarkers' pathophysiological roles as a reflection of the cardiac remodelling mechanisms in the presence of DM.
Methods
We performed the literature search to include studies from 2003 to 2021 using the following databases: MEDLINE, Scopus, Web of Science, PubMed, and Cochrane library. Articles that met our inclusion criteria were screened and appraised before being included in this review. The PRISMA guidelines for Scoping Reviews were followed.
Results
Our literature search identified a total of 43 eligible articles, which were included in this scoping review. We identified 15 different biomarkers, each described by at least two studies, that were used to determine signs of cardiac remodelling in cardiovascular disease (CVD) and people with DM. NT‐proBNP was identified as the most frequently employed biomarker in this context; however, we also identified emerging biomarkers including hs‐CRP, hs‐cTnT, and Galectin‐3.
Conclusion
There is a complex relationship between DM and cardiovascular health, where more research is needed. Current biomarkers reflective of adverse cardiac remodelling in DM are often used to diagnose other CVDs, such as NT‐proBNP for heart failure. Hence there is a need for identification of specific biomarkers that can detect early signs of cardiac remodelling in the presence of DM. Further research into these biomarkers and mechanisms can deepen our understanding of their role in DM‐associated CVD and lead to better preventative therapies.
Patients with diabetes contain a two‐three‐fold increased risk of cardiovascular disease where the one of the earliest indicators of deteriorating cardiac health is cardiac remodelling. In this scoping review, we discovered fifteen potential biomarkers that may be used as therapeutic targets for early cardiac remodelling in patients with DM. Image created with Biorender.com.
Abstract
Background and Aims
Chronic kidney disease (CKD) is an established predictor of cardiovascular disease. However, the relationship between cardiovascular disease and the early stages of CKD ...defined as stage 1 (eGFR > 90 mL/min per 1.73 m2 + albuminuria) and stage 2 (eGFR 60–89 mL/min per 1.73 m2) with and without proteinuria, is lacking. In this study, we explored the incidence of major adverse cardiovascular events (MACE), heart failure (HF) and all-cause mortality of participants with early stages of CKD in the UK Biobank population.
Method
456,015 participants from the UK Biobank were categorised into CKD stages. We calculated eGFR using the CKD-EPI 2021 equation and proteinuria was ascertained by the urinary protein creatinine ratio (defined as > 30mg/ mmol). We demonstrated the survival probability of adverse outcomes using unadjusted Kaplan-Meier curves and performed an adjusted Cox proportional hazard analysis to include MACE, HF, MACE and HF and all-cause mortality across CKD stages.
Results
Among the participants (mean age ± standard deviation, 56.5 ± 8.1 years) 282,121 (61.9%) had normal kidney function, 33,582 (7.4%) stage 1 CKD, 121,358 (26.6%) stage 2 CKD without proteinuria, 10,788 (2.4%) stage 2 CKD with proteinuria, 4,654 (1.0%) CKD stage 3A (eGFR 59-45mL/min per 1.73 m2) without proteinuria, 1034 (0.2%) stage 3A with proteinuria and 1,478 (0.3%) with more advanced CKD defined as stages 3B and above. Using Cox regression setting normal kidney function as the reference group, with the exception of stage 2 CKD without proteinuria; there was a progressive increase in the hazard ratio (HR) in all other stages of CKD with respect to MACE, HF, MACE and HF (Figure 1). Significantly, stage 2 CKD without proteinuria was associated with a lower incidence of adverse events than stage 1 CKD and had a comparable prognosis to normal renal function. There was a statistically significant association between stage 2 with proteinuria and MACE (HR 1.33, CI: 1.26 – 1.41), which was comparable to stage 3A without proteinuria (HR 1.32, CI: 1.22 – 1.42). Preliminary analysis of the ongoing cardiac magnetic resonance imaging (cMRI) data from this cohort shows similar progressive changes, apart from stage 2 CKD without proteinuria.
Conclusion
The presence of proteinuria in patients with mild CKD is a significant risk factor for MACE, HF, cMRI changes and all-cause mortality independent of age, sex, ethnicity, height, BMI, hypertension, diabetes, smoking status, and hyperlipidaemia. We recommend that in order to better risk stratify patients for prognostication and early treatment, stage 2 CKD should be considered as a significant cardiovascular risk only in the presence of proteinuria.
The African naked mole-rat (
) is unique among mammals, displaying extreme longevity, resistance to cardiovascular disease and an ability to survive long periods of extreme hypoxia. The metabolic ...adaptations required for resistance to hypoxia are hotly debated and a recent report provides evidence that they are able to switch from glucose to fructose driven glycolysis in the brain. However, other systemic alterations in their metabolism are largely unknown. In the current study, a semi-targeted high resolution
H magnetic resonance spectroscopy (MRS) metabolomics investigation was performed on cardiac tissue from the naked mole-rat (NMR) and wild-type C57/BL6 mice to better understand these adaptations. A range of metabolic differences was observed in the NMR including increased lactate, consistent with enhanced rates of glycolysis previously reported, increased glutathione, suggesting increased resistance to oxidative stress and decreased succinate/fumarate ratio suggesting reduced oxidative phosphorylation and ROS production. Surprisingly, the most significant difference was an elevation of glycogen stores and glucose-1-phosphate resulting from glycogen turnover, that were completely absent in the mouse heart and above the levels found in the mouse liver. Thus, we identified a range of metabolic adaptations in the NMR heart that are relevant to their ability to survive extreme environmental pressures and metabolic stress. Our study underscores the plasticity of energetic pathways and the need for compensatory strategies to adapt in response to the physiological and pathological stress including ageing and ischaemic heart pathologies.
Inhibiting SDH (succinate dehydrogenase), with the competitive inhibitor malonate, has shown promise in ameliorating ischemia/reperfusion injury. However, key for translation to the clinic is ...understanding the mechanism of malonate entry into cells to enable inhibition of SDH, its mitochondrial target, as malonate itself poorly permeates cellular membranes. The possibility of malonate selectively entering the at-risk heart tissue on reperfusion, however, remains unexplored.
C57BL/6J mice, C2C12 and H9c2 myoblasts, and HeLa cells were used to elucidate the mechanism of selective malonate uptake into the ischemic heart upon reperfusion. Cells were treated with malonate while varying pH or together with transport inhibitors. Mouse hearts were either perfused ex vivo (Langendorff) or subjected to in vivo left anterior descending coronary artery ligation as models of ischemia/reperfusion injury. Succinate and malonate levels were assessed by liquid chromatography-tandem mass spectrometry LC-MS/MS, in vivo by mass spectrometry imaging, and infarct size by TTC (2,3,5-triphenyl-2H-tetrazolium chloride) staining.
Malonate was robustly protective against cardiac ischemia/reperfusion injury, but only if administered at reperfusion and not when infused before ischemia. The extent of malonate uptake into the heart was proportional to the duration of ischemia. Malonate entry into cardiomyocytes in vivo and in vitro was dramatically increased at the low pH (≈6.5) associated with ischemia. This increased uptake of malonate was blocked by selective inhibition of MCT1 (monocarboxylate transporter 1). Reperfusion of the ischemic heart region with malonate led to selective SDH inhibition in the at-risk region. Acid-formulation greatly enhances the cardioprotective potency of malonate.
Cardioprotection by malonate is dependent on its entry into cardiomyocytes. This is facilitated by the local decrease in pH that occurs during ischemia, leading to its selective uptake upon reperfusion into the at-risk tissue, via MCT1. Thus, malonate's preferential uptake in reperfused tissue means it is an at-risk tissue-selective drug that protects against cardiac ischemia/reperfusion injury.
Inflammatory processes underlie many diseases associated with injury of the heart muscle, including conditions without an obvious inflammatory pathogenic component such as hypertensive and diabetic ...cardiomyopathy. Persistence of cardiac inflammation can cause irreversible structural and functional deficits. Some are induced by direct damage of the heart muscle by cellular and soluble mediators but also by metabolic adaptations sustained by the inflammatory microenvironment. It is well established that both cardiomyocytes and immune cells undergo metabolic reprogramming in the site of inflammation, which allow them to deal with decreased availability of nutrients and oxygen. However, like in cancer, competition for nutrients and increased production of signalling metabolites such as lactate initiate a metabolic cross-talk between immune cells and cardiomyocytes which, we propose, might tip the balance between resolution of the inflammation versus adverse cardiac remodeling. Here we review our current understanding of the metabolic reprogramming of both heart tissue and immune cells during inflammation, and we discuss potential key mechanisms by which these metabolic responses intersect and influence each other and ultimately define the prognosis of the inflammatory process in the heart.
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