bims-hafaim 2022-01-16 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022–01–16
twelve papers selected by
Kyle McCommis, Saint Louis University

Ulk1-dependent alternative mitophagy plays a protective role during pressure overload in the heart.
SGLT-2 inhibitors and cardiovascular outcomes in patients with and without a history of heart failure: a systematic review and meta-analysis.
Robustness of outcomes in trials evaluating sodium-glucose co-transporter 2 inhibitors for heart failure.
Calorie restriction changes lipidomic profiles and maintains mitochondrial function and redox balance during isoproterenol-induced cardiac hypertrophy.
Glucose-dependent insulinotropic polypeptide inhibits cardiac hypertrophy and fibrosis in diabetic mice via suppression of TGF-β2.
Attenuation of Adverse Postinfarction Left Ventricular Remodeling with Empagliflozin Enhances Mitochondria-Linked Cellular Energetics and Mitochondrial Biogenesis.
Time series proteome profile analysis reveals a protective role of citrate synthase in angiotensin II-induced atrial fibrillation.
Mechanisms of cardiac dysfunction in diabetic cardiomyopathy: molecular abnormalities and phenotypical variants.
Sodium-Glucose Cotransporter 2 Inhibitors and Heart Failure: A Bedside-to-Bench Journey.
Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation.
Mitochondrial protein hyperacetylation underpins heart failure with preserved ejection fraction in mice.
Serum Free Fatty Acids Independently Predict Adverse Outcomes in Acute Heart Failure Patients.

Cardiovasc Res. 2022 Jan 09. pii: cvac003. [Epub ahead of print]

Ulk1-dependent alternative mitophagy plays a protective role during pressure overload in the heart.

Jihoon Nah, Akihiro Shirakabe, Risa Mukai, Peiyong Zhai, Eun-Ah Sung, Andreas Ivessa, Wataru Mizushima, Yasuki Nakada, Toshiro Saito, Chengchen Hu, Yong-Keun Jung, Junichi Sadoshima.

   AIMS: Well-controlled mitochondrial homeostasis, including a mitochondria-specific form of autophagy (hereafter referred to as mitophagy), is essential for maintaining cardiac function. The molecular mechanism mediating mitophagy during PO is poorly understood. We have shown previously that mitophagy in the heart is mediated primarily by Atg5/Atg7-independent mechanisms, including Unc-51-like kinase1 (Ulk1)-dependent alternative mitophagy, during myocardial ischemia. Here, we investigated the role of alternative mitophagy in the heart during PO-induced hypertrophy.
METHODS AND RESULTS: Mitophagy was observed in the heart in response to transverse aortic constriction (TAC), peaking at 3-5 days. Whereas mitophagy is transiently upregulated by TAC through an Atg7-dependent mechanism in the heart, peaking at 1 day, it is also activated more strongly and with a delayed time course through an Ulk1-dependent mechanism. TAC induced more severe cardiac dysfunction, hypertrophy and fibrosis in ulk1 cardiac specific knock-out (cKO) mice than in wild type mice. Delayed activation of mitophagy was characterized by the co-localization of Rab9 dots and mitochondria and phosphorylation of Rab9 at Ser179, major features of alternative mitophagy. Furthermore, TAC-induced decreases in the mitochondrial aspect ratio were abolished and the irregularity of mitochondrial cristae was exacerbated, suggesting that mitochondrial quality control mechanisms are impaired in ulk1 cKO mice in response to TAC. TAT-Beclin 1 activates mitophagy even in Ulk1-deficient conditions. TAT-Beclin 1 treatment rescued mitochondrial dysfunction and cardiac dysfunction in ulk1 cKO mice during PO.
CONCLUSIONS: Ulk1-mediated alternative mitophagy is a major mechanism mediating mitophagy in response to PO and plays an important role in mediating mitochondrial quality control mechanisms and protecting the heart against cardiac dysfunction.
TRANSLATIONAL PERSPECTIVE: Heart failure is often accompanied by mitochondrial dysfunction in cardiomyocytes. Elimination of dysfunctional mitochondria by mitochondria-specific forms of autophagy, termed mitophagy, is a crucial mechanism for maintaining mitochondrial function in the stressed heart. We discovered that an unconventional form of mitophagy mediated through an Atg7-independent and Ulk1- and Rab9-dependent mechanism is a predominant form of mitophagy in the heart in response to pressure overload. Interventions to restore mitophagy by stimulating the signaling mechanism of the Ulk1-Rab9-dependent mitophagy should delay the development of heart failure in patients with increased afterload.

Keywords:  Cardiac hypertrophy; Rab9; Ulk1; mitochondria; mitophagy; pressure overload

DOI:  https://doi.org/10.1093/cvr/cvac003
Eur Heart J Cardiovasc Pharmacother. 2022 Jan 11. pii: pvac001. [Epub ahead of print]

SGLT-2 inhibitors and cardiovascular outcomes in patients with and without a history of heart failure: a systematic review and meta-analysis.

Victor Razuk, Mauro Chiarito, Davide Cao, Johny Nicolas, Carlo A Pivato, Anton Camaj, David Power, Frans Beerkens, Davis Jones, Aviv Alter, Alvin Mathew, Alessandro Spirito, Johanna P Contreras, George D Dangas, Roxana Mehran.

   AIMS: Sodium-glucose co-transporter 2 (SGLT-2) inhibitors have cardiovascular (CV) benefits in patients with heart failure with reduced ejection fraction (HFrEF). Whether these medications improve CV outcomes irrespective of heart failure history or left ventricular ejection fraction (LVEF) in HFrEF remains unknown.
METHODS AND RESULTS: All randomized, placebo-controlled trials of SGLT-2 inhibitors reporting similar CV outcomes were searched in PubMed from January 1, 2010 to October 1, 2021. The primary outcome was the composite of hospitalization for heart failure or CV death. Secondary outcomes included all-cause mortality. Pooled hazard ratios (HR) and 95% confidence intervals (CI) were used as effect estimates and calculated with a random-effects model. Data from eleven trials and a total of 66,957 patients (n = 36,758 SGLT-2 group, n = 30,199 placebo group) were included. SGLT-2 inhibitors reduced the risk of hospitalization for heart failure or CV death in patients with (HR 0.76 95% CI 0.71-0.80) and without (HR 0.76 95% CI 0.68-0.86; pinteraction = 0.69) heart failure. Patients with (HR 0.87 95% CI 0.80-0.95) and without (HR 0.84 95% CI 0.73-0.95; pinteraction = 0.67) heart failure treated with SGLT-2 inhibitors had a reduction in all-cause mortality. Reduction in the primary outcome was consistently observed in HFrEF patients with (HR 0.68 95% CI 0.59-0.78) and without (HR 0.84 95% CI 0.71-0.99; pinteraction = 0.13) severely reduced LVEF, and in heart failure with preserved ejection fraction patients (HR 0.80 95% CI 0.70-0.92; pinteraction = 0.65).
CONCLUSION: SGLT-2 inhibitors improved CV outcomes irrespective of heart failure history or type, and severity of LVEF reduction.PROSPERO registration: https://www.crd.york.ac.uk/prospero/CRD42020219082.

Keywords:  SGLT-2 inhibitors; diabetes mellitus; heart failure; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; left ventricular ejection fraction

DOI:  https://doi.org/10.1093/ehjcvp/pvac001
ESC Heart Fail. 2022 Jan 13.

Robustness of outcomes in trials evaluating sodium-glucose co-transporter 2 inhibitors for heart failure.

Muhammad Shariq Usman, Muhammad Shahzeb Khan, Gregg C Fonarow, Stephen J Greene, Tim Friede, Muthiah Vaduganathan, Gerasimos Filippatos, Andrew J Stewart Coats, Stefan D Anker, Javed Butler.

   AIMS: Recent trials have evaluated sodium-glucose co-transporter 2 inhibitors in patients with heart failure (HF). We sought to assess the robustness of findings from these trials using the fragility index (FI).
METHODS AND RESULTS: Fragility index is defined as the minimum number of patients that must be moved from the 'non-event' to the 'event' group to turn a statistically significant result to non-significant. In addition to FI, fragility quotient [(FQ); FI divided by the sample size] was calculated to assess the proportion of events that must be moved to change the significance. For statistically non-significant outcomes, reverse fragility index (RFI) and reverse fragility quotient (RFQ) were calculated. Robustness of findings after pooling data from all three trials was also assessed. A robust reduction in first HF hospitalization or cardiovascular mortality was seen with dapagliflozin (FI = 62 and FQ = 0.013), empagliflozin (FI = 50 and FQ = 0.013), and sotagliflozin (FI = 60 and FQ = 0.049). Dapagliflozin nominally improved all-cause and cardiovascular mortality, with modest FI (n = 8 and 5) and FQ (0.002 and 0.001). Empagliflozin and sotagliflozin did not demonstrate statistically significant reductions in all-cause mortality, with modest RFI (empagliflozin: RFI = 26 and RFQ = 0.007; sotagliflozin: RFI = 6 and RFQ = 0.005). A similar trend was seen with cardiovascular mortality (empagliflozin: RFI = 24 and RFQ = 0.006; sotagliflozin: RFI = 7 and RFQ = 0.006). Upon meta-analysis, the result for first HF hospitalization or cardiovascular mortality was robust (FI = 95 and FQ = 0.010). The reductions in all-cause (FI = 12 and FQ = 0.001) and cardiovascular mortality (FI = 9 and FQ = 0.001), while statistically significant, were fragile.
CONCLUSION: Improvement in the composite outcome of first HF hospitalization or cardiovascular death was highly concordant and robust across sodium-glucose co-transporter 2 inhibitor trials. In contrast, secondary endpoints of all-cause and cardiovascular mortality were statistically fragile, underscoring the need to power trials for mortality to fully understand the benefit of therapies on fatal events.

Keywords:  Cardiac failure; Fragility index; Robustness; Sodium-glucose co-transporter 2 inhibitors

DOI:  https://doi.org/10.1002/ehf2.13785
J Physiol Biochem. 2022 Jan 13.

Calorie restriction changes lipidomic profiles and maintains mitochondrial function and redox balance during isoproterenol-induced cardiac hypertrophy.

Cícera Edna Barbosa David, Aline Maria Brito Lucas, Pedro Lourenzo Oliveira Cunha, Yuana Ivia Ponte Viana, Marcos Yukio Yoshinaga, Sayuri Miyamoto, Adriano Brito Chaves Filho, Anna Lídia Nunes Varela, Alicia Juliana Kowaltowski, Heberty Tarso Facundo.

  Typically, healthy cardiac tissue utilizes more fat than any other organ. Cardiac hypertrophy induces a metabolic shift leading to a preferential consumption of glucose over fatty acids to support the high energetic demand. Calorie restriction is a dietary procedure that induces health benefits and lifespan extension in many organisms. Given the beneficial effects of calorie restriction, we hypothesized that calorie restriction prevents cardiac hypertrophy, lipid content changes, mitochondrial and redox dysregulation. Strikingly, calorie restriction reversed isoproterenol-induced cardiac hypertrophy. Isolated mitochondria from hypertrophic hearts produced significantly higher levels of succinate-driven H2O2 production, which was blocked by calorie restriction. Cardiac hypertrophy lowered mitochondrial respiratory control ratios, and decreased superoxide dismutase and glutathione peroxidase levels. These effects were also prevented by calorie restriction. We performed lipidomic profiling to gain insights into how calorie restriction could interfere with the metabolic changes induced by cardiac hypertrophy. Calorie restriction protected against the consumption of several triglycerides (TGs) linked to unsaturated fatty acids. Also, this dietary procedure protected against the accumulation of TGs containing saturated fatty acids observed in hypertrophic samples. Cardiac hypertrophy induced an increase in ceramides, phosphoethanolamines, and acylcarnitines (12:0, 14:0, 16:0, and 18:0). These were all reversed by calorie restriction. Altogether, our data demonstrate that hypertrophy changes the cardiac lipidome, causes mitochondrial disturbances, and oxidative stress. These changes are prevented (at least partially) by calorie restriction intervention in vivo. This study uncovers the potential for calorie restriction to become a new therapeutic intervention against cardiac hypertrophy, and mechanisms in which it acts.

Keywords:  Antioxidants; Calorie restriction; Cardiac hypertrophy; Free radicals; Lipidome; Mitochondria

DOI:  https://doi.org/10.1007/s13105-021-00863-4
Diab Vasc Dis Res. 2021 Mar-Apr;18(2):18(2): 1479164121999034

Glucose-dependent insulinotropic polypeptide inhibits cardiac hypertrophy and fibrosis in diabetic mice via suppression of TGF-β2.

Munenori Hiromura, Yusaku Mori, Michishige Terasaki, Hideki Kushima, Tomomi Saito, Naoya Osaka, Hironori Yashima, Makoto Ohara, Tomoyasu Fukui, Takanori Matsui, Sho-Ichi Yamagishi.

  Diabetic cardiomyopathy is associated with an increased risk for heart failure and death in patients with diabetes. We investigated here whether and how GIP attenuated cardiac hypertrophy and fibrosis in diabetic mice with obesity. Diabetic db/db mice at 7 weeks old were infused with vehicle or GIP (50 nmol/kg/day) for 6 weeks, and hearts were collected for histological and RT-PCR analyzes. Cardiomyocytes isolated from neonatal mice were incubated with or without 300 nM [D-Ala2]-GIP, 30 mM glucose, or 100 μg/mL advanced glycation end products (AGEs) for RT-PCR and lucigenin assays. Compared with non-diabetic mice, diabetic mice exhibited larger left ventricle wall thickness and cardiomyocyte sizes and more fibrotic areas in association with up-regulation of myosin heavy chain β (β-Mhc) and transforming growth factor-beta2 (Tgf-β2) mRNA levels, all of which were inhibited by GIP infusion. High glucose increased NADPH oxidase-driven superoxide generation and up-regulated β-Mhc, Tgf-β2, and receptor for AGEs mRNA levels in cardiomyocytes, and augmented the AGE-induced β-Mhc gene expression. [D-Ala2]-GIP attenuated all of the deleterious effects of high glucose and/or AGEs on cardiomyocytes. Our present findings suggest that GIP could inhibit cardiac hypertrophy and fibrosis in diabetic mice via suppression of TGF-β2.

Keywords:  AGEs; GIP; RAGE; diabetic cardiomyopathy; oxidative stress

DOI:  https://doi.org/10.1177/1479164121999034
Int J Mol Sci. 2021 Dec 31. pii: 437. [Epub ahead of print]23(1):

Attenuation of Adverse Postinfarction Left Ventricular Remodeling with Empagliflozin Enhances Mitochondria-Linked Cellular Energetics and Mitochondrial Biogenesis.

Yang Song, Chengqun Huang, Jon Sin, Juliana de F Germano, David J R Taylor, Reetu Thakur, Roberta A Gottlieb, Robert M Mentzer, Allen M Andres.

  Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as empagliflozin are known to reduce the risk of hospitalizations related to heart failure irrespective of diabetic state. Meanwhile, adverse cardiac remodeling remains the leading cause of heart failure and death in the USA. Thus, understanding the mechanisms that are responsible for the beneficial effects of SGLT2 inhibitors is of the utmost relevance and importance. Our previous work illustrated a connection between adverse cardiac remodeling and the regulation of mitochondrial turnover and cellular energetics using a short-acting glucagon-like peptide-1 receptor agonist (GLP1Ra). Here, we sought to determine if the mechanism of the SGLT2 inhibitor empagliflozin (EMPA) in ameliorating adverse remodeling was similar and/or to identify what differences exist, if any. To this end, we administered permanent coronary artery ligation to induce adverse remodeling in wild-type and Parkin knockout mice and examined the progression of adverse cardiac remodeling with or without EMPA treatment over time. Like GLP1Ra, we found that EMPA affords a robust attenuation of PCAL-induced adverse remodeling. Interestingly, unlike the GLP1Ra, EMPA does not require Parkin to improve/maintain mitochondria-related cellular energetics and afford its benefits against developing adverse remodeling. These findings suggests that further investigation of EMPA is warranted as a potential path for developing therapy against adverse cardiac remodeling for patients that may have Parkin and/or mitophagy-related deficiencies.

Keywords:  Parkin; adverse remodeling; empagliflozin; mitochondrial biogenesis; mitophagy

DOI:  https://doi.org/10.3390/ijms23010437
J Hypertens. 2022 Jan 10.

Time series proteome profile analysis reveals a protective role of citrate synthase in angiotensin II-induced atrial fibrillation.

Fei Teng, Xiao Han, Peng Yu, Pang-Bo Li, Hui-Hua Li, Yun-Long Zhang.

BACKGROUND: Angiotensin (Ang) II and elevated blood pressure are considered to be the main risk factors for atrial fibrillation. However, the proteome profiles and key mediators/signaling pathways involved in the development of Ang II-induced atrial fibrillation remain unclear.
METHODS: Male wild-type C57BL/6 mice (10-week old) were infused with Ang II (2000 ng/kg per min) for 1, 2, or 3 weeks, respectively. Time series proteome profiling of atrial tissues was performed using isobaric tags for relative and absolute quantitation and liquid chromatography coupled with tandem mass spectrometry.
RESULTS: We identified a total of 1566 differentially expressed proteins (DEPs) in the atrial tissues at weeks 1, 2, and 3 after Ang II infusion. These DEPs were predominantly involved in mitochondrial oxidation-reduction and tricarboxylic acid cycle in Ang II-infused atria. Moreover, coexpression network analysis revealed that citrate synthase, a rate-limiting enzyme in the tricarboxylic acid cycle, was localized at the center of the mitochondrial oxidation-reduction process, and its expression was significantly downreguated in Ang II-infused atria at different time points. Cardiomyocyte-specific overexpresion of citrate synthase markedly reduced atrial fibrillation susceptibility and atrial remodeling in mice. These beneficial effects were associated with increased ATP production and mitochondrial oxidative phosphorylation system complexes I-V expression and inhibition of oxidative stress.
CONCLUSION: The current study defines the dynamic changes of the DEPs involved in Ang II-induced atrial fibrillation, and identifies that citrate synthase plays a protective role in regulating atrial fibrillation development, and increased citrate synthase expression may represent a potential therapeutic option for atrial fibrillation treatment.

DOI: https://doi.org/10.1097/HJH.0000000000003075
Heart Fail Rev. 2022 Jan 10.

Mechanisms of cardiac dysfunction in diabetic cardiomyopathy: molecular abnormalities and phenotypical variants.

Francesca Romana Prandi, Isabella Evangelista, Domenico Sergi, Alberto Palazzuoli, Francesco Romeo.

  Diabetic cardiomyopathy (DCM) is a diabetes mellitus-induced pathophysiological condition characterized by cardiac structural, functional, and metabolic changes that can result in heart failure (HF), in the absence of coronary artery disease, hypertension, and valvular heart disease. Metabolic alterations such as hyperglycemia, insulin resistance, hyperinsulinemia, and increased metabolism of free fatty acids result in oxidative stress, inflammation, advanced glycation end products formation, abnormalities in calcium homeostasis, and apoptosis that are responsible for structural remodeling. Cardiac stiffness, hypertrophy, and fibrosis eventually lead to dysfunction and HF with preserved ejection fraction and/or HF with reduced ejection fraction. In this review, we analyzed in detail the cellular and molecular mechanisms and the metabolic pathways involved in the pathophysiology of DCM. Different phenotypes are observed in DCM, and it is not clear yet if the restrictive and the dilated phenotypes are distinct or represent an evolution of the same disease. Phenotypic differences can be observed between T1DM and T2DM DCM, possibly explained by the different myocardial insulin action. Further studies are needed in order to better understand the underlying mechanisms of DCM and to identify appropriate therapeutic targets and novel strategies to prevent and reverse the progression toward heart failure in diabetic patients.

Keywords:  Diabetes mellitus; Diabetic cardiomyopathy; Heart failure; Restrictive phenotype

DOI:  https://doi.org/10.1007/s10741-021-10200-y
Front Cardiovasc Med. 2021 ;8 810791

Sodium-Glucose Cotransporter 2 Inhibitors and Heart Failure: A Bedside-to-Bench Journey.

Donato Cappetta, Antonella De Angelis, Gabriella Bellocchio, Marialucia Telesca, Eleonora Cianflone, Daniele Torella, Francesco Rossi, Konrad Urbanek, Liberato Berrino.

  Type 2 diabetes mellitus (T2DM) and heart failure (HF) are multifactorial diseases sharing common risk factors, such as obesity, hyperinsulinemia, and inflammation, with underlying mechanisms including endothelial dysfunction, inflammation, oxidative stress, and metabolic alterations. Cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors observed in diabetic and non-diabetic patients are also related to their cardiac-specific, SGLT-independent mechanisms, in addition to the metabolic and hemodynamic effects. In search of the possible underlying mechanisms, a research campaign has been launched proposing varied mechanisms of action that include intracellular ion homeostasis, autophagy, cell death, and inflammatory processes. Moreover, the research focus was widened toward cellular targets other than cardiomyocytes. At the moment, intracellular sodium level reduction is the most explored mechanism of direct cardiac effects of SGLT2 inhibitors that mediate the benefits in heart failure in addition to glucose excretion and diuresis. The restoration of cardiac Na+ levels with consequent positive effects on Ca2+ handling can directly translate into improved contractility and relaxation of cardiomyocytes and have antiarrhythmic effects. In this review, we summarize clinical trials, studies on human cells, and animal models, that provide a vast array of data in support of repurposing this class of antidiabetic drugs.

Keywords:  clinical trials; diabetes; heart failure; sodium and calcium overload; sodium-glucose cotransporter 2 inhibitor

DOI:  https://doi.org/10.3389/fcvm.2021.810791
Int J Mol Sci. 2022 Jan 04. pii: 547. [Epub ahead of print]23(1):

Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation.

Jun H Heo, Sang R Lee, Seong Lae Jo, Hyun Yang, Hye Won Lee, Eui-Ju Hong.

  Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced β-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from β-oxidation to glycolysis, may induce cardiac structural remodeling.

Keywords:  cardiac hypertrophy; glycolysis; letrozole; β-oxidation

DOI:  https://doi.org/10.3390/ijms23010547
J Mol Cell Cardiol. 2022 Jan 05. pii: S0022-2828(22)00001-3. [Epub ahead of print]165 76-85

Mitochondrial protein hyperacetylation underpins heart failure with preserved ejection fraction in mice.

Xin Liu, Yabing Zhang, Yan Deng, Lin Yang, Wei Ou, Maodi Xie, Lin Ding, Chunling Jiang, Hai Yu, Qian Li, Tao Li.

  Over 50% of patients with heart failure have preserved ejection fraction (HFpEF), rather than reduced ejection fraction (HFrEF). The prevalence of HFpEF continues to increase, while the pathogenic mechanisms underlying HFpEF remain largely elusive and evidence-based therapies are still lacking. This study was designed to investigate the metabolic signature of HFpEF and test the potential therapeutic intervention in a mouse model. By utilizing a "3-Hit" HFpEF mouse model, we observed a global protein hyperacetylation in the HFpEF hearts as compared to the pressure overload-induced HFrEF and adult/aged non-heart failure (NHF) hearts. Acetylome analysis identified that a large proportion of the hyperacetylated proteins (74%) specific to the HFpEF hearts are in mitochondria, and enriched in tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and fatty acid oxidation. Further study showed that the elevated protein acetylation in the HFpEF hearts was correlated with reduced NAD+/NADH ratio, impaired mitochondrial function, and depleted TCA cycle metabolites. Normalization of NAD+/NADH ratio by supplementation of nicotinamide riboside (NR) for 30 days downregulated the acetylation level, improved mitochondrial function and ameliorated HFpEF phenotypes. Therefore, our study identified a distinct protein acetylation pattern in the HFpEF hearts, and proposed NR as a promising agent in lowering acetylation and mitigating HFpEF phenotypes in mice.

Keywords:  Heart failure; Mitochondria; NAD(+); Nicotinamide riboside; Protein acetylation

DOI:  https://doi.org/10.1016/j.yjmcc.2021.12.015
Front Cardiovasc Med. 2021 ;8 761537

Serum Free Fatty Acids Independently Predict Adverse Outcomes in Acute Heart Failure Patients.

Yi Yu, Chunna Jin, Chengchen Zhao, Shiyu Zhu, Simin Meng, Hong Ma, Jian'an Wang, Meixiang Xiang.

  Background: Perturbation of energy metabolism exacerbates cardiac dysfunction, serving as a potential therapeutic target in congestive heart failure. Although circulating free fatty acids (FFAs) are linked to insulin resistance and risk of coronary heart disease, it still remains unclear whether circulating FFAs are associated with the prognosis of patients with acute heart failure (AHF). Methods: This single-center, observational cohort study enrolled 183 AHF patients (de novo heart failure or decompensated chronic heart failure) in the Second Affiliated Hospital, Zhejiang University School of Medicine. All-cause mortality and heart failure (HF) rehospitalization within 1 year after discharge were investigated. Serum FFAs were modeled as quartiles as well as a continuous variable (per SD of FFAs). The restricted cubic splines and cox proportional hazards models were applied to evaluate the association between the serum FFAs level and all-cause mortality or HF rehospitalization. Results: During a 1-year follow-up, a total of 71 (38.8%) patients had all-cause mortality or HF rehospitalization. The levels of serum FFAs positively contributed to the risk of death or HF rehospitalization, which was not associated with the status of insulin resistance. When modeled with restricted cubic splines, the serum FFAs increased linearly for the incidence of death or HF rehospitalization. In a multivariable analysis adjusting for sex, age, body-mass index, coronary artery disease, diabetes mellitus, hypertension, left ventricular ejection fraction and N-terminal pro-brain natriuretic peptid, each SD (303.07 μmol/L) higher FFAs were associated with 26% higher risk of death or HF rehospitalization (95% confidence interval, 2-55%). Each increasing quartile of FFAs was associated with differentially elevated hazard ratios for death or HF rehospitalization of 1 (reference), 1.71 (95% confidence interval, [0.81, 3.62]), 1.41 (95% confidence interval, [0.64, 3.09]), and 3.18 (95% confidence interval, [1.53, 6.63]), respectively. Conclusion: Serum FFA levels at admission among patients with AHF were associated with an increased risk of adverse outcomes. Additional studies are needed to determine the causal-effect relationship between FFAs and acute cardiac dysfunction and whether FFAs could be a potential target for AHF management.

Keywords:  Lipolysis; Mortality; acute heart failure; free fatty acids; rehospitalization

DOI:  https://doi.org/10.3389/fcvm.2021.761537