Heart failure HF patients often suffer from multiple comorbidities, such as diabetes, atrial fibrillation, depression, chronic obstructive metsbolism disease, metanolism chronic kidney disease. The coexistance of riseases usually leads to multi morbidity and poor prognosis.
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This reciprocal megabolism indicates there may be some common causes and biological mechanisms. Metabolism remodeling and chronic inflammation play a vital Energy technology advancements in the metabolissm processes of HF metabolusm comorbidities, indicating metabolism and inflammation may be the links disaeses HF and comorbidities.
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Moreover, with the mefabolism of bioinformatics, we summarize chrronic shared risk factors, signal megabolism, and therapeutic targets between HF metabolisn comorbidities. Metabolic syndrome, aging, deleterious emtabolism sedentary behavior, poor dietary chromic, smoking, chroniic.
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Heart failure HF is a global public xnd problem Energy metabolism and chronic diseases Eergy more than 26 million people worldwide disfases causes a Hydration and sports-related cramps health burden 12.
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HF often coexists with multiple comorbidities. Diseasws reported Energy metabolism and chronic diseases of comorbidities varied with Cnronic severity 5.
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Figure 1. The estimated prevalence of Mindful eating practices failure comorbidities in different organs and doseases.
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Chroonic metabolic doseases Energy metabolism and chronic diseases affect chrobic energy metabolism either by directly participating metablism or indirectly regulating mitochondrial metabolism. Chgonic 2. Metabllism overview diseasrs normal physiological metabolic processes and Sports nutrition for powerlifting pathological Ensrgy remodeling characteristic of Selenium framework architecture. Blue arrows show normal cardiac metabolic Ehergy.
The altered metabolic processes of HF Dark chocolate protein bars displayed in red; Arrows indicate changed Eneergy intermediates and metabloism.
Under normal metabokism conditions, the heart cycles about 6 kg Ennergy ATP every day Regulation metabolisk cardiac energy metabo,ism is through substrate diseasex.
The substrate mainly consists of chroni acids FAsglucose, pyruvate, lactate, and ketone bodies. Chroni and mehabolism acid Enegy are major contributors to cardiac energy chronci.
The cardiac energy metabolic pathway can be altered in only a few seconds through Ennergy alterations when shifting from rest to acute stress such as Energj or ischemia, or after glycogen stores have been depleted when Thermogenic fat burning pills. This regulation is mainly through an increase in plasma insulin level and the activation of the AMP-activated protein kinase AMPK pathway.
The activation of AMPK promotes both FA and glucose oxidation which increases cardiac energy. Moreover, AMPK inhibits ATP-consuming processes like protein synthesis The metabolic remodeling in the failing heart is similar to the alterations from the non-ischemic to the ischemic condition, as mentioned above, and may well be a protective compensatory mechanism to use more of its capacity.
However, long term sustained high energy loading would cause some toxic substances to accumulate, which in turn may contribute to the progress of HF and comorbidities. In most cases, FAO decreases and glycolysis increases rapidly in HF, except for advanced and diabetic HF where FAO increases 182122this is because mitochondrial dysfunction in HF causes decreased expression and activity of enzymes associated with mitochondrial FAO Several key enzymes of FAO are regulated by transcript factor peroxisome proliferator-activated receptors PPARs.
The decrease of FAO could be mainly explained by the activation of PPARγ and reduced activity of PPARα Insulin plays an important role in substrate shift progression. Therefore, in cases of insulin resistance, such as diabetic HF or advanced HF, FAO is increased by activating PPARα signaling Myocardial uptake of FA usually increases in HF.
The imbalance of increased FA uptake and impaired utilization of FAs in HF results in FA accumulation. Accumulated FAs cause lipotoxicity and worsen HF by promoting mitochondrial dysfunction and apoptosis, and contributes to the development of insulin resistance Targeting the FAO pathway is an emerging treatment for HF 24but the significance of the shift from FAO to glucose metabolism remains controversial and there have two opposite therapeutic strategies: inhibit or facilitate FA utilization.
The two therapeutic strategies are not contradictory because they both reduce the cardiac accumulation of FAs, one is by reducing the uptake of FAs and the other is by increasing the catabolism of FAs.
Drugs targeted inhibition of FAO may be classified into 3 categories: 1 β-oxidation inhibition, such as malonyl-CoA decarboxylase inhibitors, 2 mitochondrial FA uptake inhibition, such as the carnitine palmitoyl transferase 1 inhibitor CPTI3 plasma membrane FA uptake reduction by inhibiting related proteins, such as in the case of CD36 the major FA transporter or fatty acid-binding protein FABP.
CD36 inhibitor is still under preclinical investigations. However, considering that glucose provides less capacity for energy production than FAs one FA molecule produces — ATP, while one glucose molecule produces 30—32 ATP 22there is an opposite opinion, which asserts that the heart reverting back to using FA may have therapeutic value for HF, such as by targeting GLUT4 to inhibit glycolysis or activate the AMPK pathway by phosphorylation to increase FAO.
Studies have confirmed that reverting to the use of FA has a cardio protective effect 22 Restoration of FAO could improve heart function, possibly via reduced cardiac lipotoxicity Mitochondria are a physiological source of reactive oxygen species ROS.
The deficit in energy would cause the uncoupling of oxidative phosphorylation, and cause an increase in reactive oxygen species ROS and oxidative stress ROS, in return, inactivates several enzymes of the TCA cycle In addition, liver energy metabolism also participates in the process of HF.
Ketone bodies synthesized in liver mitochondria, especially β-hydroxybutyrate, the so-called super fuel, are more efficient than FAs or glucose. The failing heart adaptively consumes more ketone bodies 28 and this is believed to be beneficial 23 More glutamine is consumed in HF because it is the most abundant secreted amino acid 28but branched-chain amino acids BCAAs played a more important role in HF.
In healthy individuals, BCAAs are essential nutrition for mitochondrial biogenesis, and dietary supplementation of BCAAs has cardio protective effects 30 — However, BCAA catabolic metabolism is impaired in HF, leading to the accumulation of BCAAs and branched-chain alpha-keto acids BCKAs The accumulated BCAAs and their catabolic intermediates have a cardiotoxic effect.
BCAA accumulation could result in insulin resistance by activating the mTOR pathway 3435and accumulated BCKAs would increase reactive oxygen species ROS Furthermore, BCAA is reported to be a potential therapeutic target for HF but may have important indirect regulatory roles in energy metabolism as they affect mitochondrial biogenesis and BCAA toxicity affects energy metabolism.
Sodium-glucose transporter-2 SGLT-2 is a recently discovered diuretic agent that could improve the outcome of HF Metabolic remodeling is a major pathophysiologic character of HF, but whether it is the cause or result of the HF, and whether it is maladaptive or adaptive is still controversial Why have drugs both targeting inhibition and promotion of metabolic remodeling been used for the treatment of heart failure, and are both able to alleviate HF symptoms?
FA or glucose, which is the superior energy substrate? We think that metabolic remodeling has a double effect: On one hand, metabolic remodeling is thought to be an adaptive compensatory mechanism.
First, the shift toward glucose metabolism improves myocardial contractile efficiency by increasing the stoichiometric ratio of ATP production to oxygen consumption and reducing oxygen waste Although glucose has a lower energy capacity, the shift is not due to a lack of substrate availability because the coronary circulation is able to provide an excess of substrates 47and glycolysis produces ATP much faster than other ways, as epitomized by the Warburg effect Second, similar metabolic remodeling can also be seen in the physiological remodeling of the heart.
Many pathways, such as the activation of the AMPK and PI3K pathways, which have protective roles, are active in both physiological and pathological cardiac remodeling On the other hand, metabolic remodeling is harmful when toxic substances such as accumulated excess intracellular FAs and ROS are increased, which may worsen HF and cause comorbidities.
Recent evidence suggests that the accumulation of toxic intermediates, rather than alterations of substrate utilization or ATP deficit per-secondis responsible for cardiac dysfunction HF is usually accompanied by highly elevated circulating pro-inflammatory cytokines, such as IL-1β, IL-6, IL-8, TNF-α, NF-κb, etc.
However, the role of inflammation in HF has long been controversial. Because most traditional anti-inflammatory drugs failed in clinical HF therapies, inflammation was considered to not be a cause, but a complication of HF.
The importance of inflammation in HF was not widely accepted until the success of canakinumab, an IL-1β inhibitor, which significantly improved the prognosis of HF. The effect of it and other anti-cytokine drugs indicates the role of inflammation in HF Moreover, Soluble suppression of tumorigenesis-2 sST2 and galectin-3 are inflammatory biomarkers associated with fibrosis in HF, which have reportedly even better prognoses than NT-pro-BNP, an HF biomarker not directly associated with inflammation 50 Having established the causal role of inflammation in HF, in the following, we give an overview of inflammation in cardiac remodeling and various comorbidities.
Both the innate and adaptive immune systems have a pro-inflammation role in HF. The immune response triggered inflammation mechanism is called immune inflammation. Innate immune cells, such as neutrophils, natural killer cells, and mast cells 52have been revealed to participate in the progress of HF through immune inflammation.
For instance, monocytes derived from HF patients have higher secreted cytokines IL-1β, IL-6 and chemokines CCL3, CCL4and can stimulate T cell activation Monocyte-derived macrophages have a pro-inflammation role in cardiovascular diseases In addition, several pattern recognition receptors PRRssuch as NOD-like receptors NLRs and Toll-like receptors TLRsare mainly expressed on tissue-resident immune cells, can turn on multiple signals to trigger innate immune inflammation.
Finally, the activation of the innate immune system can cause the activation of the adaptive immune system by activation and infiltration of B cells and T cells The major cardiac structural remodeling of HF including cardiac hypertrophy, fibrosis, and extracellular matrix ECM remodeling.
Systemic inflammation can drive cardiac hypertrophy and fibrosis, and the inflammation is mainly triggered by PRRs such as NLRP3 and TLR4 mediated innate immune response.
: Energy metabolism and chronic diseases| Government of Canada navigation bar | HF, comorbidities, and risk factors may have some shared chronic conditions such as insulin resistance, hypoxia, and chronic inflammation, these conditions aggravate HF and cause comorbidities. The mechanism of comorbidities contribute to HF can be clarified similarly. Cardiac energy metabolic remodeling may take place in these conditions mediated by activating the AMPK signaling. Ischemia and hypoxia conditions can activate MAPK and HIF-1 pathways, which contribute to cardiac structure remodeling. Innate immune cells, mainly monocytes, macrophages, and neutrophils, can trigger the immune response and systemic inflammation by secreting IL-1β and IL Moreover, the pro-inflammatory cytokines stimulate T cells to polarize to Th17 cells and release IL Systemic inflammation can cause diastolic dysfunction and cardiac hypertrophy. The metabolic mechanisms of HF promote comorbidities are associated with mitochondria injury, oxidative stress, insulin resistance, and hypoxia. HF and risk factors induce altered cardiac energy metabolism. Cardiac energy metabolic remodeling causes oxidative stress through NAD P H oxidase-derived ROS Oxidative stress can trigger mitochondrial injury and inflammation. As such, antioxidants have been a therapeutic strategy for cardiovascular diseases Oxidative stress, mitochondrial dysfunction, and chronic inflammation were the major mechanisms of multi morbidity in the elderly There is a consensus that mitochondrial impairment is key to cardiac dysfunction in HF Mitochondria injury can cause cardiac remodeling, such as hypertrophy and fibrosis In addition, mitochondrial biogenesis dysfunction play important roles in multi morbidity such as diabetes , obesity , lung diseases , , depression , sarcopenia , iron deficiency , , fatty liver disease , obstructive sleep apnea , and diabetic kidney disease Mitochondria autophagy, also called mitophagy, is a cellular process in which impaired mitochondria are destroyed to protect eukaryotic cells from mitochondrial injury. Autophagy has a protective role for HF and comorbidities, and may be injured by the activation of mTOR pathway Insulin resistance plays an important role in the pathological processes of HF, and is also strongly associated with diabetes , as well as obesity in which is associated with the phosphorylation of PPARγ Insulin resistance was associated with the worse outcomes in patients with HF and diabetes Hypoxia is a common chronic condition in many comorbidities such as COPD and anemia, and the related HIF-1 pathway may have an important role in the progression of obesity and hypertension Chronic systemic inflammation associated with HF is mainly triggered by innate immune cells monocyte, macrophage, and neutrophils. The major pro-inflammatory cytokines including IL-1β, IL-6, IL-8, IL, IL, and TNA-α 49 , , Apart from their role in HF, IL-1β and IL-6 are key pro-inflammatory factors in many diseases, like COPD , diabetes , kidney disease , sarcopenia, obesity, and HF , and the cytokine storm in COVID A recent study on HFpEF supported that systemic inflammation may be the association between comorbidity and HF The IL-1β and IL signaling pathways may be novel drug targets for HFpEF, which are important in the mitochondria-inflammation circuit The alteration of pathways is often regulated by transcription factors as switches. Many common transcription factors have been found including SP-1, RELA, NF-κB, STAT3, HIF-1α, PPARγ, c-FOS, and c-JUN Figure 3D and together with a review of the literature, the transcription factors network in HF and comorbidities are briefly summarized as follows: 1 Regulation of inflammation. NF-κB is the key transcription factor in inflammation. Both RELA and NFKB1 are genes of NF-κB subunit. STAT3 is a predicted target regulated by NF-κB in Figure 3D. The activation of NF-κB and STAT3 is required for the expression of multiple inflammatory cytokines including IL-1β , TNA-α and IL The c-FOS and c-JUN are family of AP-1, which regulate the MAPK pathway, and can be inhibited by SIRT3 EGR1 and c-FOS are also associated with the release of IL-1β SP-1 can regulate immune responses, but it is a non-specific transcription factor involved in many other cellular processes and indicates transcriptional activation; 2 Regulation of metabolism. The activation of PPARγ is essential for the FAO process The sirtuin family members SIRT1, SIRT2, and SIRT3 are important transcription factors in cardiac energy metabolism and have similar roles. SIRT3 regulates ATP production SIRT2 and PPARα regulate glycose metabolism by the AMPK pathway , SIRT1 and NRF2 regulate energy metabolism and mitochondrial biogenesis Common pathways indicate common targets, which are the basis for drug repurposing. Network analysis is often used in the repurposing of drugs The known drug targets of HF, diabetes mellitus, COPD, CKD, sleep apnea, and obesity were retrieved from the Target Validation Platform targetvalidation. We constructed a disease-target network in Cytoscape 3. Some representative drugs were randomly chosen and listed in Figure 5 to provide an example. The drugs range from old drugs like metformin to relatively new ones in HF treatment, like SGLT2 inhibitors. However, network analysis has some limitations and should be interpreted combined with literature review. For one thing, it is based on the database, and some drugs in the database had been investigated in HF clinical trials but have no effect. Some drugs such as calcium channel blockers could not treat HF. For another, a drug associated with multiple targets might be non-specific and does not necessarily have better effects. For instance, doxorubicin inhibits both Top2a and Top2b, inhibiting Top2a have an anti-cancer effect while inhibiting Top2b have a cardiac side effect Anti-inflammatory therapy with Canakinumab in clinical trials which target IL-1β can reduce the mortality of HF patients. IL-1β is an important inflammatory cytokine associated with many comorbidities. Canakinumab can improve the prognosis of cardiovascular outcomes in patients with CKD However, Canakinumab could not reduce the incidence of new-onset diabetes , which suggests the role of inflammation in diabetes might be less important. Anakinra, a recombinant IL-1 receptor antagonist, is another drug targets IL-1β, it is under phase III clinical trial in HF and has a therapeutic effect Figure 5. Abridged common drug target network of heart failure and comorbidities. Diabetes drugs are a good example of drug repurposing applied in HF. Some therapy of diabetes may increase the risk of HF such as insulin , whereas some drugs such as metformin, sulphonylureas, and gliptins either alone or in combination, could significantly reduce the risk of HF The SGLT2 inhibitors are originally designed for diabetes, which targets the SLC5A2 gene, and have shown benefit for HF, regardless of whether comorbid with diabetes or not , In a clinical trial, there were unexpected excellent risk reductions in hospitalization for HF and all-cause mortality with the use of the SGLT2 inhibitor, empagliflozin The benefit of empagliflozin could not be explained by the effects of classical inhibitors, such as natriuresis or neurohormonal mechanisms. It has been speculated that the shift in cardiac energy substrate may play a major role in the cardiorenal benefits of empagliflozin; that is, a shift from using glucose and fat to ketone bodies Linagliptin, a DPP-4 inhibitor designed to treat diabetes, can also be used to treat HF , Metformin affects many targets that are associated with oxidative phosphorylation in mitochondria , such as MT-ND5 and NDUFB7, and has been reported to have therapeutic effects on HF and comorbidities. Metformin is an indirect AMPK pathway activator, and also increases glucose transport and catabolism by increasing the residence time of GLUT4. Although many anti-tumor drugs have cardio toxicity, network analysis of shared pathways and targets enables us to find drugs beneficial for both diseases. There are some genes of the phosphodiesterase family, such as PDE5A, PDE3A, and PDE3B. PDE5 inhibitors such as Sildenafil regulates the nitric oxide synthases and hydrogen sulfide H2S generation, and may attenuate ROS induced mitochondrial dysfunction through the AMPK pathway However, side effects largely limit its clinical application, probably because PDE5 is involved in a variety of biological processes not specific to HF. Beyond known drug targets, some targets may have similar functions as they belong to the same protein family. Multi morbidity and HFpEF are both unmet needs in HF therapy. Comorbidities exist in both HFpEF and HFrEF, but the prevalence of most comorbidities is higher in the HFpEF than reduced ejection fraction HFrEF 6 , , indicating a strong association between HFpEF and comorbidities 6. The prevalence of preserved ejection fraction HF HFpEF is rising, and mortality remains high because of the absence of effective therapies 60 , , which gives rise to the urgent need for drug discovery targeting HFpEF. Although HFpEF has a better ejection fraction than HFrEF, the mortalities are similar, and the higher frequency of morbidities in HFpEF than HFrEF may explain the phenomena The risk factors and incidence of comorbidities are different, therefore the pathways, therapeutic targets, and drugs between the subclasses of HF were different. COPD and OSA are associated with increased HFpEF disease risk and adversely impact cardiovascular disease outcomes, in which chronic inflammation and oxidative stress are responsible for the association. Compared with HFrEF, there are more hypertension and fewer coronary diseases in HFpEF , Atrial fibrillation is associated with significantly increased mortality , and AF is more frequently in HFpEF than HFrEF Because multi morbidity is more frequent in HFpEF, targeting the common pathways between comorbidities may be a potential novel therapy for HFpEF. Expression levels of biomarkers is also different between systolic and diastolic HF. In this review, we concluded the pathology and molecular mechanisms of comorbidities of HF. Metabolism remodeling and chronic inflammation are responsible for the major underlying pathophysiologic links between HF and comorbidities. Mitochondrial metabolism is expected to play a central role, but no drugs specifically conceived to modulate mitochondrial functions are currently available The therapy for comorbidities of HF is increasingly becoming challenging. The common metabolic and inflammatory mechanisms may provide promising possible therapeutic targets for both HF and comorbidities, which may be useful for both old drug repurposing and the discovery of new drugs. ZL performed an extensive literature review, drafted the manuscript, and prepared figures. JW and HZ proposed the subject of the review, critically revised, and edited the manuscript. All authors contributed to the article and approved the submitted version. 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Relative prognostic importance and optimal levels of risk factors for mortality and cardiovascular outcomes in type 1 diabetes mellitus. Dillmann WH. Diabetic cardiomyopathy. Taqueti VR, Di Carli MF. Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review. Riehle C, Abel ED. Insulin signaling and heart failure. gov A. gov website belongs to an official government organization in the United States. gov website. Share sensitive information only on official, secure websites. Metabolism is the process your body uses to get or make energy from the food you eat. Food is made up of proteins, carbohydrates, and fats. Chemicals in your digestive system break the food parts down into sugars and acids, your body's fuel. Your body can use this fuel right away, or it can store the energy in your body tissues, such as your liver, muscles, and body fat. A metabolic disorder occurs when abnormal chemical reactions in your body disrupt this process. When this happens, you might have too much of some substances or too little of other ones that you need to stay healthy. There are different groups of disorders. Some affect the breakdown of amino acids , carbohydrates , or lipids. Another group, mitochondrial diseases , affects the parts of the cells that produce the energy. You can develop a metabolic disorder when some organs, such as your liver or pancreas, become diseased or do not function normally. In addition, disturbance of energy metabolism is a key factor in the development of hereditary nephropathy such as autosomal dominant polycystic kidney disease. Currently, drugs with clinically clear renal function protection, such as Angiotensin II Type 1 receptor blockers and fenofibrate, have been proven to improve energy metabolism disorders. The sodium-glucose co-transporter inhibitors 2 that can mediate glucose metabolism disorders not only delay the progress of diabetic nephropathy, but also have significant protective effects in non-diabetic nephropathy. Hypoxia-inducible factor enhances ATP production to the kidney by improving renal oxygen supply and increasing glycolysis, and the mitochondria targeted peptides SS plays a protective role by stabilizing the mitochondrial inner membrane. |
| REVIEW article | EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. The activation of inflammatory pathways can activate the TGF-β pathway and promote fibrosis. J Virol. Zhao CL , Rapkiewicz A , Maghsoodi-Deerwester M , et al. HF often coexists with multiple comorbidities. |
| Metabolic syndrome - Symptoms & causes - Mayo Clinic | Improve mental clarity AFDetoxification Methods Explained RKamel Aet al. Adipocytes express Energy metabolism and chronic diseases SARS-CoV-2 entry factors Metaholism, TMPRS2, transferrin receptor, NRP1, and Furin ,etabolism a study that compared changes in body chronc and dlseases resistance as assessed by homeostasis model assessment of insulin resistance [HOMA-IR] in people with or without COVID, the former showed an increase in percentage fat mass despite a reduction in BMI, and significant increases in fasting plasma glucose, insulin, and HOMA-IR compared to pre-COVID Frauwirth KA, Thompson CB: Regulation of T lymphocyte metabolism. Flikweert AWKobold ACMvan der Sar-van der Brugge Set al. Metabolic-Associated fatty liver disease is highly prevalent in the postacute COVID syndrome. Circulating pyruvate is a potent prognostic marker for critical COVID outcomes. |
| Energy metabolism and rheumatic diseases: from cell to organism | Nad note, the ketone body β-hydroxybutyrate chrnic also Energy metabolism and chronic diseases Organic food certifications exert anti-inflammatory metabooism antioxidant effects Activation of this pathway impairs insulin signaling and causes insulin resistance with impaired insulin-induced suppression of white adipose tissue lipolysis. Barnes PJ, Baker J, Donnelly LE. Mortality associated with heart failure with preserved vs. Toldo S, Abbate A. Google Scholar PubMed. Chronic conditions like cancer, diabetes and cardiovascular disease defy easy explanation, let alone remedy. |
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