Driving force of deteriorated cellular environment in heart failure: Metabolic remodeling

Fan, Lu; Meng, Chenchen; Wang, Xiaoming; Wang, Yunjiao; Li, Yanyang; Lv, Shichao; Zhang, Junping

doi:10.1016/j.clinsp.2023.100263

Lu Fan

wrote the paper draft

agree to be accountable for all aspects of work ensuring integrity and accuracy

declare that all data were generated in-house and that no paper mill was used

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China

National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China

https://orcid.org/0000-0002-9493-6410

Chenchen Meng

drew the figures

agree to be accountable for all aspects of work ensuring integrity and accuracy

declare that all data were generated in-house and that no paper mill was used

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China

National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China

Xiaoming Wang

drew the figures

agree to be accountable for all aspects of work ensuring integrity and accuracy

declare that all data were generated in-house and that no paper mill was used

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China

National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China

Yunjiao Wang

drew the tables

agree to be accountable for all aspects of work ensuring integrity and accuracy

declare that all data were generated in-house and that no paper mill was used

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China

National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China

Yanyang Li

drew the tables

agree to be accountable for all aspects of work ensuring integrity and accuracy

declare that all data were generated in-house and that no paper mill was used

Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

Shichao Lv ^** Corresponding author. E-mail address:dr_lv@foxmail.com (S. Lv).

corrected the draft

agree to be accountable for all aspects of work ensuring integrity and accuracy

declare that all data were generated in-house and that no paper mill was used

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China

Tianjin Key Laboratory of Traditional Research of TCM Prescription and Syndrome, Tianjin, China

https://orcid.org/0000-0002-4073-9083

Junping Zhang

corrected the draft

agree to be accountable for all aspects of work ensuring integrity and accuracy

declare that all data were generated in-house and that no paper mill was used

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China

* Corresponding author. E-mail address:dr_lv@foxmail.com (S. Lv).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Population	Baseline	Main findings	Ref.
Fatty acid
HF (n = 8)	chronic, severe AHA/ACC Stage D HF	Decreased abundance of medium to long-chain acylcarnitines in the failing hearts;	^[34]34 Bedi KC Jr, Snyder NW, Brandimarto J, Aziz M, Mesaros C, Worth AJ, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation. 2016;133(8):706-16.
HF (n = 8)	chronic, severe AHA/ACC Stage D HF	Decreased succinyl-CoA and increased acetyl-CoA in end-stage failing myocardium
HF (n = 18)	A 10-month history of IDCM;	Unchanged oxidative metabolism in HF;	^[114]114 Tuunanen H, Engblom E, Naum A, Någren K, Hesse B, Airaksinen KE, et al. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation. 2006;114(20):2130-7.
HF (n = 18)	Mean NYHA class: 2.2	Significantly decreased efficiency of patients
CHF (n = 12)	Stable NYHA class III;	Higher myocardial fatty acid uptake in patients with HF;	^[115]115 Taylor M, Wallhaus TR, Degrado TR, Russell DC, Stanko P, Nickles RJ, et al. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in patients with congestive heart failure. J Nucl Med. 2001;42(1):55-62.
CHF (n = 12)	LVEF ≤35%	Elevated serum FFA
HF (n = 19)	A 10-month history of IDCM;	Reduced myocardial FFA metabolism;	^[116]116 Tuunanen H, Engblom E, Naum A, Scheinin M, Någren K, Airaksinen J, et al. Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction. J Card Fail. 2006;12(8):644-52.
HF (n = 19)	Mean NYHA class: 2.2	Reduced myocardial FFA metabolism;
HFrEF (n = 15)	Mean age: 71 ± 6 years;	Unimpaired FFA oxidation;	^[78]78 Voros G, Ector J, Garweg C, Droogne W, Van Cleemput J, Peersman N, et al. Increased cardiac uptake of ketone bodies and free fatty acids in human heart failure and hypertrophic left ventricular remodeling. Circ Heart Fail. 2018;11(12):e004953.
HFrEF (n = 15)	LVEF: 28 ± 8%	Significantly increased cardiac uptake of ketone bodies
Glucose
non-ischemic HF (n = 8)	Mean age: 40.5 ± 11.5 years;	Diminished glucose metabolism in failing hearts;	^[117]117 Weitzel LB, Ambardekar AV, Brieke A, Cleveland JC, Serkova NJ, Wischmeyer PE, et al. Left ventricular assist device effects on metabolic substrates in the failing heart. PLoS One. 2013;8(4):e60292.
	Failing heart: LVEF 10%;	Recovered their values post-LVAD
	Post-LVAD heart: LVEF 26%
CHF (n = 10)	Mean age: 60.6 ± 1.1 years;	Impaired glucose handling;	^[80]80 Zordoky BN, Sung MM, Ezekowitz J, Mandal R, Han B, Bjorndahl TC, Alberta HEART. Metabolomic fingerprint of heart failure with preserved ejection fraction. PLoS One. 2015;10(5):e0124844.
CHF (n = 10)	NYHA class ≥ II	Decreased insulin-mediated stimulation of total-body oxidative glucose metabolism
Ketone body
HF (n = 46)	LVEF: 39.59 ± 10.94%;	Significantly increased hydroxybutyrate and acetone levels	^[80]80 Zordoky BN, Sung MM, Ezekowitz J, Mandal R, Han B, Bjorndahl TC, Alberta HEART. Metabolomic fingerprint of heart failure with preserved ejection fraction. PLoS One. 2015;10(5):e0124844.
HF (n = 46)	NYHA class ≥ II	Significantly increased hydroxybutyrate and acetone levels
HF (n = 615)	Low acetoacetate group (n = 302): LVEF 52 ± 16%;	High levels of circulating acetoacetate were associated with older age, higher NYHA classification, hypertension, high B-type natriuretic peptide levels, and worse clinical outcome.	^[118]118 Yokokawa T, Yoshihisa A, Kanno Y, Abe S, Misaka T, Yamada S, et al. Circulating acetoacetate is associated with poor prognosis in heart failure patients. Int J Cardiol Heart Vasc. 2019;25:100432.
HF (n = 615)	High acetoacetate group (n = 313): LVEF 50 ± 16%

Animal model	Intervention	Events	Cardiac outcome	Ref.
Fatty acid
Rats with post-infarction HF	CAL	Markedly decreased myocardial mRNA expression of H-FABP and MCAD	Cardiac compensated remodeling	^[119]119 Rosenblatt-Velin N, Montessuit C, Papageorgiou I, Terrand J, Lerch R Postinfarction heart failure in rats is associated with upregulation of GLUT-1 and downregulation of genes of fatty acid metabolism. Cardiovasc Res. 2001;52(3):407-16.
DS rats with CHF	TAC	Decreased gene expression of PPARα, PGC1-α and fatty acid transporter	Compensated LVH;	^[120]120 Kato T, Niizuma S, Inuzuka Y, Kawashima T, Okuda J, Tamaki Y, et al. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ Heart Fail. 2010;3(3):420-30.
DS rats with CHF	Fed a high-salt diet		Decreased cardiac PCr/ATP
C57BL/6 mice with HF	TAC	Rapid normalization of cardiac oxidative metabolism	Cardiac fibrosis;	^[121]121 Byrne NJ, Levasseur J, Sung MM, Masson G, Boisvenue J, Young ME, et al. Normalization of cardiac substrate utilization and left ventricular hypertrophy precede functional recovery in heart failure regression. Cardiovasc Res. 2016;110(2):249-57.
C57BL/6 mice with HF	TAC	Rapid normalization of cardiac oxidative metabolism	Severe exercise intolerance
C57BL/6N mice with HF	TAC	Elevated rates of systemic FA utilization	Cardiac fibrosis;	^[122]122 Sung MM, Byrne NJ, Robertson IM, Kim TT, Samokhvalov V, Levasseur J, et al. Resveratrol improves exercise performance and skeletal muscle oxidative capacity in heart failure. Am J Physiol Heart Circ Physiol. 2017;312(4):H842-H853.
C57BL/6N mice with HF	TAC	Elevated rates of systemic FA utilization	Exercise intolerance
C57BL/6 mice with HF	Post-infarction (MCD-KO & CAL)	Almost unchanged rates of glycogen degradation, glycogen synthesis, TG degradation and synthesis	Systolic dysfunctions;	^[123]123 Masoud WG, Ussher JR, Wang W, Jaswal JS, Wagg CS, Dyck JR, et al. Failing mouse hearts utilize energy inefficiently and benefit from improved coupling of glycolysis and glucose oxidation. Cardiovasc Res. 2014;101(1):30-8.
C57BL/6 mice with HF	Post-infarction (MCD-KO & CAL)		Reduced LVEF
Obese C57BL/6J mice with HF	AAC	FAO dominated as source of ATP production	Cardiac insulin resistance;	^[124]124 Sankaralingam S, Abo Alrob O, Zhang L, Jaswal JS, Wagg CS, Fukushima A, et al. Lowering body weight in obese mice with diastolic heart failure improves cardiac insulin sensitivity and function: implications for the obesity paradox. Diabetes. 2015;64(5):1643-57.
Obese C57BL/6J mice with HF	Fed a high-fat diet	FAO dominated as source of ATP production	Developed diastolic dysfunction
Glucose
C57BL/6 mice with HF	AAC	Reduction insulin-stimulated glucose utilization;	Marked cardiac insulin resistance;	^[32]32 Zhang L, Jaswal JS, Ussher JR, Sankaralingam S, Wagg C, Zaugg M, et al. Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy. Circ Heart Fail. 2013;6(5):1039-48.
		Impaired plasma membrane translocation of GLUT4;	Marked cardiac insulin resistance;
		Elevated glycolysis	Developed diastolic dysfunction
C57/Bl6 mice with HF	TAC	Reduced rates of glucose and lactate oxidation;	Systolic dysfunction;	^[125]125 Zhabyeyev P, Gandhi M, Mori J, Basu R, Kassiri Z, Clanachan A, et al. Pressure-overload-induced heart failure induces a selective reduction in glucose oxidation at physiological afterload. Cardiovasc Res. 2013;97(4):676-85.
C57/Bl6 mice with HF	TAC	Unchanged glycolysis or FAO	Diastolic dysfunction
DS rats with HFpEF	Fed a high salt diet	Increased glycolysis;	Cardiac hypertrophy;	^[126]126 Fillmore N, Levasseur JL, Fukushima A, Wagg CS, Wang W, Dyck JRB, et al. Uncoupling of glycolysis from glucose oxidation accompanies the development of heart failure with preserved ejection fraction. Mol Med. 2018;24(1):3.
		Unchanged glucose oxidation rates;	Diastolic dysfunction
		Increased GLUT1 expression	Diastolic dysfunction
DS rats with CHF	Fed a high-salt diet	Increased glucose uptake and decreased fatty acid uptake;	Concentric LVH;	^[120]120 Kato T, Niizuma S, Inuzuka Y, Kawashima T, Okuda J, Tamaki Y, et al. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ Heart Fail. 2010;3(3):420-30.
DS rats with CHF	Fed a high-salt diet	Decreased expression of GLUT4 and increased GLUT1	Cardiac dysfunction
Ketone body
C57BL/6J mice with HF	TAC & post-infarction	Increased expression of BDH 1;	Reduced left ventricular systolic function;	^[33]33 Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, et al. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133(8):698-705.
		Decreased gene expression involved in FA utilization;	Reduced left ventricular systolic function;
		Accumulated mitochondrial ketone oxidation	Global chamber dilatation
C57BL/6J mice with HF	AAC	Elevated βOHB level;	Cardiac dysfunction;	^[127]127 Nagao M, Toh R, Irino Y, Mori T, Nakajima H, Hara T, et al. β-Hydroxybutyrate elevation as a compensatory response against oxidative stress in cardiomyocytes. Biochem Biophys Res Commun. 2016;475(4):322-8.
C57BL/6J mice with HF	AAC	Down-regulated SCOT	Adverse cardiac remodeling

Agent	Mechanism of action	Drug class	Objects	Key results	Ref.
Trimetazidine	FAO inhibition	LC3-KAT inhibitor;	HF (n = 955)	Significantly reduced left ventricular end-systolic volume;	^[128]128 Gao D, Ning N, Niu X, Hao G, Meng Z Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart. 2011;97(4):278-86.
		LC3-KAT inhibitor;	HF (n = 955)	Improved NYHA class
		Weak CPTI inhibitor	HF (n = 44)	Improved NYHA class and quality of life;	^[129]129 Fragasso G, Salerno A, Lattuada G, Cuko A, Calori G, Scollo A, et al. Effect of partial inhibition of fatty acid oxidation by trimetazidine on whole body energy metabolism in patients with chronic heart failure. Heart. 2011;97(18):1495-500.
		Weak CPTI inhibitor	HF (n = 44)	Reduction in whole body REE
Ranolazine	FAO inhibition	LC3-KAT inhibitor	HFpEF (n = 20)	Significantly decreased LVEDP vs. placebo;	^[130]130 Maier LS, Layug B, Karwatowska-Prokopczuk E, Belardinelli L, Lee S, Sander J, et al. RAnoLazIne for the treatment of diastolic heart failure in patients with preserved ejection fraction: the RALI-DHF proof-of-concept study. JACC Heart Fail. 2013;1(2):115-22.
			HFpEF (n = 20)	Improved measures of hemodynamics
			CHF (n = 109);	Significantly improved LVEF;	^[131]131 Murray GL, Colombo J Ranolazine preserves and improves left ventricular ejection fraction and autonomic measures when added to guideline-driven therapy in chronic heart failure. Heart Int. 2014;9(2):66-73.
			NYHA class: II‒IV	Decreased SB
Pemafibrate	FAO stimulation	SPPARM-α	T2D (n ≈ 10,000)	On going (PROMINENT)	^[92]92 Pradhan AD, Paynter NP, Everett BM, Glynn RJ, Amarenco P, Elam M, et al. Rationale and design of the pemafibrate to reduce cardiovascular outcomes by reducing triglycerides in patients with diabetes (PROMINENT) study. Am Heart J. 2018;206:80-93.
			ApoE2KI mice;	Exerting beneficial effects on FAO, RCT and inflammation	^[132]132 Hennuyer N, Duplan I, Paquet C, Vanhoutte J, Woitrain E, Touche V, et al. The novel selective PPARα modulator (SPPARMα) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis. Atherosclerosis. 2016;249:200-8.
			HapoA-I tg mice	Exerting beneficial effects on FAO, RCT and inflammation
Metformin	Glucose oxidation stimulation	Hypoglycaemic agent	HF (n = 34,504)	Small reduction in all-cause hospitalization;	^[133]133 Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold L, et al. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail. 2013;6(3):395-402.
			HF (n = 34,504)	Reduced mortality;
			CKD (n = 5);	Reduced HF readmission in patients with CKD or CHF;	^[93]93 Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron CB, Stanifer JW, Mock CK, et al. Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: a systematic review. Ann Intern Med. 2017;166(3):191-200.
			CHF (n = 11);	Reduced HF readmission in patients with CKD or CHF;
			CLD (n = 3)	Reduced all-cause mortality
Empagliflozin	Enhanced renal glucose excretion;	SGLT2i	HF (n = 3730);	Reduced risk of cardiovascular death or hospitalization for HF	^[134]134 Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al.; EMPEROR-reduced trial investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413-24.
Empagliflozin	Enhanced renal glucose excretion;		NYHA class: II‒IV
Dapagliflozin	Increased circulating KB and FFA		HFrEF (n = 4744)	Reduced risk of cardiovascular death or worsening HF	^[135]135 Berg DD, Jhund PS, Docherty KF, Murphy SA, Verma S, Inzucchi SE, et al. Time to clinical benefit of dapagliflozin and significance of prior heart failure hospitalization in patients with heart failure with reduced ejection fraction. JAMA Cardiol. 2021;6(5):499-507.
Sotagliflozin	Increased circulating KB and FFA	SGLT1/2i	Worsening HF (n = 1222)	Reduced risk of cardiovascular death or worsening HF	^[136]136 Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al.; SOLOIST-WHF trial investigators. sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384(2):117-28.
Mito Q	Mitochondrial ROS scavenging	Selective mitochondria targeted antioxidant	HF (n = 2149)	Reduced mortality;	^[103]103 Lei L, Liu Y Efficacy of coenzyme Q10 in patients with cardiac failure: a meta-analysis of clinical trials. BMC Cardiovasc Disord. 2017;17(1):196.
			HF (n = 2149)	Improved exercise capacity
			HF (n = 420)	Reduced cardiovascular mortality, all-cause mortality and incidence of hospital stays for HF;	^[137]137 Mortensen SA, Rosenfeldt F, Kumar A, Dolliner P, Filipiak KJ, Pella D, et al.; Q-SYMBIO study investigators. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail. 2014;2(6):641-9.
			HF (n = 420)	Significantly improved NYHA class
NR	Improving mitochondrial function	NAD⁺ Repletion	C57BL/6N mice with HFpEF	Alleviated mitochondrial dysfunction;	^[106]106 Tong D, Schiattarella GG, Jiang N, Altamirano F, Szweda PA, Elnwasany A, et al. NAD+ repletion reverses heart failure with preserved ejection fraction. Circ Res. 2021;128(11):1629-41.
			C57BL/6N mice with HFpEF	Improved cardiac function
			Stage D HF (n = 19)	Improved mitochondrial respiration;	^[138]138 Zhou B, Wang DD, Qiu Y, Airhart S, Liu Y, Stempien-Otero A, O'Brien KD, Tian R Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure. J Clin Invest. 2020;130(11):6054-63.
			Stage D HF (n = 19)	Alleviated proinflammatory activation of PBMCs

[1] * Corresponding author. E-mail address:dr_lv@foxmail.com (S. Lv).

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Driving force of deteriorated cellular environment in heart failure: Metabolic remodeling

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