bims-hafaim 2024-09-22 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2024–09–22
eight papers selected by
Kyle McCommis, Saint Louis University

Ketone Body Metabolism is Not Required for Improvement of Heart Failure by Ketogenic Diet in Mice.
Cardiac function and energetics in mice with combined genetic augmentation of creatine and creatine kinase activity.
Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.
Impaired insulin sensitivity measured by estimated glucose disposal rate is associated with decreased myocardial mechano-energetic efficiency in non-diabetic individuals.
Cardiometabolic benefits of fenofibrate in heart failure related to obesity and diabetes.
Maternal Ketone Supplementation Throughout Gestation Improves Neonatal Cardiac Dysfunction Caused by Perinatal Iron Deficiency.
Deciphering metabolomics and lipidomics landscape in zebrafish hypertrophic cardiomyopathy model.
Synergistically improved cardiovascular outcomes in type 2 diabetes mellitus patients with combined treatment of SGLT-2 inhibitors and pioglitazone.

bioRxiv. 2024 Sep 02. pii: 2024.08.30.610511. [Epub ahead of print]

Ketone Body Metabolism is Not Required for Improvement of Heart Failure by Ketogenic Diet in Mice.

Zachary Foulks, Carla J Weinheimer, Attila Kovacs, Jessica Michael, Kelly D Pyles, Thiago N Menezes, Kevin Cho, Gary J Patti, Kyle S McCommis.

Failing hearts increasingly metabolize ketone bodies, and enhancing ketosis improves heart failure (HF) remodeling. Circulating ketones are elevated by fasting/starvation, which is mimicked with a high-fat, low-carbohydrate "ketogenic diet" (KD). While speculated that KD improves HF through increased ketone oxidation, some evidence suggests KD paradoxically downregulates cardiac ketone oxidation despite increased ketone delivery. We sought to clarify the significance of cardiac ketone metabolism during KD in HF. Mice were subjected to transverse aortic constriction with apical myocardial infarction (TAC-MI) and fed either low-fat (LF) control or KD. Cardiac-specific mitochondrial pyruvate carrier 2 (csMPC2-/-) mice were used as a second model of heart failure. In both mice, feeding a KD improved HF, determined by echocardiography, heart weights, and gene expression analyses. Although KD increases plasma ketone bodies, gene expression for ketone metabolic genes is decreased in the hearts of KD-fed mice. Cardiac-specific β-hydroxybutyrate dehydrogenase 1 (csBDH1-/-), the first enzyme in ketone catabolism, mice were also studied and crossed with the csMPC2-/- mice to create double knockout (DKO) mice. These mice were aged to 16 weeks and switched to LF or KD, and KD was able to completely normalize the hearts of both csMPC2-/- and DKO mice, suggesting that ketone metabolism is unnecessary for improving heart failure with ketogenic diet. These studies were then repeated, and mice injected with U-13C-β-hydroxybutyrate to evaluate ketone metabolism. KD feeding significantly decreased the enrichment of the TCA cycle from ketone body carbons, as did the BDH1-deletion in DKO mice. Gene expression and respirometry suggests that KD instead increases cardiac fat oxidation. In conclusion, these results suggest that ketogenic diet decreases cardiac ketone metabolism and does not require ketone metabolism to improve heart failure.

DOI: https://doi.org/10.1101/2024.08.30.610511
J Mol Cell Cardiol. 2024 Sep 12. pii: S0022-2828(24)00155-X. [Epub ahead of print]196 105-114

Cardiac function and energetics in mice with combined genetic augmentation of creatine and creatine kinase activity.

Sevasti Zervou, Debra J McAndrew, Hannah A Lake, Elina Kuznecova, Christopher Preece, Benjamin Davies, Stefan Neubauer, Craig A Lygate.

  Improving energy provision in the failing heart by augmenting the creatine kinase (CK) system is a desirable therapeutic target. However, over-expression of the creatine transporter (CrT-OE) has shown that very high creatine levels result in cardiac hypertrophy and dysfunction. We hypothesise this is due to insufficient endogenous CK activity to maintain thermodynamically favourable metabolite ratios. If correct, then double transgenic mice (dTg) overexpressing both CrT and the muscle isoform of CK (CKM-OE) would rescue the adverse phenotype. In Study 1, overexpressing lines were crossed and cardiac function assessed by invasive haemodynamics and echocardiography. This demonstrated that CKM-OE was safe, but too few hearts had creatine in the toxic range. In Study 2, a novel CrT-OE line was generated with higher, homogeneous, creatine levels and phenotyped as before. Myocardial creatine was 4-fold higher in CrT-OE and dTg hearts compared to wildtype and was associated with hypertrophy and contractile dysfunction. The inability of dTg hearts to rescue this phenotype was attributed to downregulation of CK activity, as occurs in the failing heart. Nevertheless, combining both studies in a linear regression analysis suggests a modest positive effect of CKM over a range of creatine concentrations. In conclusion, we confirm that moderate elevation of creatine is well tolerated, but very high levels are detrimental. Correlation analysis lends support to the theory that this may be a consequence of limited CK activity. Future studies should focus on preventing CKM downregulation to unlock the potential synergy of augmenting both creatine and CK in the heart.

Keywords:  Creatine kinase; Creatine transporter; Energetics; Metabolism; Myocardial function; SLC6A8; Transgenic mice

DOI:  https://doi.org/10.1016/j.yjmcc.2024.09.007
Nat Cardiovasc Res. 2024 Sep 18.

Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.

Khanh V Doan, Timothy S Luongo, Thato T Ts'olo, Won Dong Lee, David W Frederick, Sarmistha Mukherjee, Gabriel K Adzika, Caroline E Perry, Ryan B Gaspar, Nicole Walker, Megan C Blair, Nicole Bye, James G Davis, Corey D Holman, Qingwei Chu, Lin Wang, Joshua D Rabinowitz, Daniel P Kelly, Thomas P Cappola, Kenneth B Margulies, Joseph A Baur.

Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.

DOI: https://doi.org/10.1038/s44161-024-00542-9
Eur J Intern Med. 2024 Sep 16. pii: S0953-6205(24)00386-8. [Epub ahead of print]

Impaired insulin sensitivity measured by estimated glucose disposal rate is associated with decreased myocardial mechano-energetic efficiency in non-diabetic individuals.

Chiara M A Cefalo, Alessia Riccio, Teresa Vanessa Fiorentino, Elena Succurro, Maria Perticone, Angela Sciacqua, Francesco Andreozzi, Giorgio Sesti.

   BACKGROUND AND AIMS: Impaired myocardial mechano-energetic efficiency (MEE) has been associated with cardiac insulin resistance measured by dynamic positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) combined with euglycemic-hyperinsulinemic clamp. Estimate glucose disposal rate (eGDR) index has a good correlation with whole-body insulin sensitivity. It remains unsettled whether eGDR index is a suitable proxy of cardiac insulin sensitivity as well as its association with myocardial MEE. The aims of this study were: 1) to compare eGDR index with HOMA-IR, QUICKI and FIRI indexes for association with myocardial glucose metabolic rate (MrGlu); and 2) to determine the association of eGDR index with myocardial MEE.
METHODS: We evaluated MrGlu using PET with 18F-FDG combined with euglycemic-hyperinsulinemic clamp in 50 individuals without history of coronary heart disease. Myocardial MEE per gram of left ventricular mass (MEEi) was measured in 1181 subjects by echocardiography. eGDR (mg kg-1/min) was calculated as: 21.158 - (0.09 × waist circumference in cm) - (3.407 × hypertension, 1 = yes 0 = no) - (0.551 × HbA1c%).
RESULTS: eGDR index was more strongly associated with myocardial MrGlu than HOMA-IR, QUICKI, and FIRI indexes (r = -0.662, r = -0.492, r = 0.570, and r = -0.492, respectively). Individuals in the lower tertiles of eGDR exhibited a significant reduction of MEEi as compared to those in the highest tertile (P < 0.001). In a stepwise multivariate linear regression analysis eGDR index was the major determinant of MEEi independently of well-established cardio-metabolic risk factors.
CONCLUSIONS: These data suggest that the eGDR index may be a useful marker to identifying individuals at high cardiovascular risk.

Keywords:  Cardiac energetics; Cardiovascular disease; Estimated glucose disposal rate; Impaired glucose tolerance; Insulin-resistance; Myocardial energetic efficiency

DOI:  https://doi.org/10.1016/j.ejim.2024.09.008
Cardiovasc Diabetol. 2024 Sep 16. 23(1): 343

Cardiometabolic benefits of fenofibrate in heart failure related to obesity and diabetes.

Jiwon Park, Hangyul Song, Shinje Moon, Yumin Kim, Sungsoo Cho, Kyungdo Han, Cheol-Young Park, Sung Woo Cho, Chang-Myung Oh.

   BACKGROUND: Heart failure (HF) is a serious and common condition affecting millions of people worldwide, with obesity being a major cause of metabolic disorders such as diabetes and cardiovascular disease. This study aimed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, on the obese- and diabetes-related cardiomyopathy.
METHODS AND RESULTS: We used db/db mice and high fat diet-streptozotocin induced diabetic mice to investigate the underlying mechanisms of fenofibrate's beneficial effects on heart function. Fenofibrate reduced fibrosis, and lipid accumulation, and suppressed inflammatory and immunological responses in the heart via TNF signaling. In addition, we investigated the beneficial effects of fenofibrate on HF hospitalization. The Korean National Health Insurance database was used to identify 427,154 fenofibrate users and 427,154 non-users for comparison. During the 4.22-year follow-up, fenofibrate use significantly reduced the risk of HF hospitalization (hazard ratio, 0.907; 95% CI 0.824-0.998).
CONCLUSIONS: The findings suggest that fenofibrate may be a useful therapeutic agent for obesity- and diabetes-related cardiomyopathy.

Keywords:  Diabetic cardiomyopathy; Fenofibrate; Heart failure

DOI:  https://doi.org/10.1186/s12933-024-02417-6
Clin Sci (Lond). 2024 Sep 17. pii: CS20241386. [Epub ahead of print]

Maternal Ketone Supplementation Throughout Gestation Improves Neonatal Cardiac Dysfunction Caused by Perinatal Iron Deficiency.

Ronan Noble, Shubham Soni, Si Ning Liu, Jad-Julian Rachid, Heather E Mast, Alyssa Widemeyer, Claudia Holody, Richard Mah, Andrew Woodman, Mourad Ferdaoussi, Helene Lemieux, Jason R B Dyck, Stephane L Bourque.

  Iron deficiency (ID) is common during gestation and in early infancy and has been shown to adversely affect cardiac development and function, which could lead to lasting cardiovascular consequences. Ketone supplementation has been shown to confer cardioprotective effects in numerous disease models. Here we tested the hypothesis that maternal ketone supplementation during gestation would mitigate cardiac dysfunction in ID neonates. Female Sprague Dawley rats were fed an iron-restricted or iron-replete diet before and throughout pregnancy. Throughout gestation, iron-restricted dams were given either a daily subcutaneous injection of ketone solution (containing β-hydroxybutyrate [βOHB]) or saline (vehicle). Neonatal offspring cardiac function was assessed by echocardiography at postnatal days (PD)3 and 13. Hearts and livers were collected post-mortem for assessments of mitochondrial function and gene expression profiles of markers oxidative stress and inflammation. Maternal iron restriction caused neonatal anemia and asymmetric growth restriction at all time points assessed, and maternal βOHB treatment had no effect on these outcomes. Echocardiography revealed reduced ejection fraction despite enlarged hearts (relative to body weight) in ID offspring, resulting in impaired oxygen delivery, which was attenuated by maternal βOHB supplementation. Further, maternal ketone supplementation affected biochemical markers of mitochondrial function, oxidative stress and inflammation in hearts of neonates, implicating these pathways in the protective effects conferred by βOHB. In summary, βOHB supplementation confers protection against cardiac dysfunction in ID neonates, and could have implications for the treatment of anemic babies.

Keywords:  anemia; cardiac function; iron deficiency; ketone; neonate; pregnancy

DOI:  https://doi.org/10.1042/CS20241386
Sci Rep. 2024 09 19. 14(1): 21902

Deciphering metabolomics and lipidomics landscape in zebrafish hypertrophic cardiomyopathy model.

Shana Jacob, Tala Abuarja, Rulan Shaath, Waseem Hasan, Saroja Balayya, Doua Abdelrahman, Khalid Almana, Hajira Afreen, Ahmad Hani, Michail Nomikos, Khalid Fakhro, Mohamed A Elrayess, Sahar Isa Da'as.

  To elucidate the lipidomic and metabolomic alterations associated with hypertrophic cardiomyopathy (HCM) pathogenesis, we utilized cmybpc3-/- zebrafish model. Fatty acid profiling revealed variability of 10 fatty acids profiles, with heterozygous (HT) and homozygous (HM) groups exhibiting distinct patterns. Hierarchical cluster analysis and multivariate analyses demonstrated a clear separation of HM from HT and control (CO) groups related to cardiac remodeling. Lipidomic profiling identified 257 annotated lipids, with two significantly dysregulated between CO and HT, and 59 between HM and CO. Acylcarnitines and phosphatidylcholines were identified as key contributors to group differentiation, suggesting a shift in energy source. Untargeted metabolomics revealed 110 and 53 significantly dysregulated metabolites. Pathway enrichment analysis highlighted perturbations in multiple metabolic pathways in the HM group, including nicotinate, nicotinamide, purine, glyoxylate, dicarboxylate, glycerophospholipid, pyrimidine, and amino acid metabolism. Our study provides comprehensive insights into the lipidomic and metabolomic unique signatures associated with cmybpc3-/- induced HCM in zebrafish. The identified biomarkers and dysregulated pathways shed light on the metabolic perturbations underlying HCM pathology, offering potential targets for further investigation and potential new therapeutic interventions.

Keywords:  Hypertrophic cardiomyopathy; Lipidomics; MYBPC3; Metabolomics; Zebrafish

DOI:  https://doi.org/10.1038/s41598-024-72863-5
Front Endocrinol (Lausanne). 2024 ;15 1420485

Synergistically improved cardiovascular outcomes in type 2 diabetes mellitus patients with combined treatment of SGLT-2 inhibitors and pioglitazone.

Yan-Rong Li, Chih-Ching Wang, Chi-Hung Liu, Chieh-Li Yen, Victor Chien-Chia Wu, Evelyn Jou-Chen Huang, Ching-Yu Lee, Ching-Chung Hsiao.

   Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have cardiovascular (CV) benefits, particularly in reducing the risk of heart failure (HF). Pioglitazone (Pio) has shown potential in decreasing the risks of recurrent stroke, non-fatal myocardial infarction (MI), and all-cause mortality but increasing risks of HF. Our study aimed to examine the synergistic effects on CV outcomes in patients with type 2 diabetes mellitus (T2DM) who received the combined treatment of SGLT2i and Pio.
Materials and methods: A total of 117,850 patients with T2DM and without a history of HF were selected as the observational study cohort from the Chang Gung Research Database (CGRD) in Taiwan between January 1, 2016, and December 31, 2019. The primary composite outcome was 4-point major adverse CV events (4P-MACE), including CV death, non-fatal MI, non-fatal ischemic stroke, and hospitalization for HF. The study was divided into four groups: a combined treatment group in which SGLT2i and Pio were used, two individual groups in which SGLT2i or Pio was used separately, and a reference group (non-study drugs).
Results: Combined treatment of SGLT2i and Pio had the lowest risk of 4P-MACE (adjusted hazard ratio [aHR], 0.66; 95% confidence interval [CI], 0.54-0.80) compared with the reference group after a mean follow-up of 2.2 years. There was no significant difference in risks of hospitalization for HF (adjusted subdistribution hazard ratio, 0.73; 95% CI, 0.49-1.07) compared with the reference group.
Conclusions: In T2DM patients without HF, the combined treatment with SGLT2i and Pio may synergistically provide CV benefits without increasing risks of HF.

Keywords:  cardiovascular outcomes; heart failure; pioglitazone; sodium-glucose co-transporter-2 inhibitors (SGLT2i); type 2 diabetes mellitus

DOI:  https://doi.org/10.3389/fendo.2024.1420485