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 Table of Contents  
Year : 2020  |  Volume : 4  |  Issue : 4  |  Page : 100-108

Emerging role of natriuretic peptides in diabetes mellitus: New approaches for risk stratification

1 Internal Medicine Department, State Medical University, Ministry of Health of Ukraine, Zaporozhye, Ukraine
2 Internal Medicine Department, Medical Academy of Post-Graduate Education, Ministry of Health of Ukraine, Zaporozhye, Ukraine

Date of Submission16-Jan-2020
Date of Acceptance24-Aug-2020
Date of Web Publication13-Oct-2020

Correspondence Address:
Prof. Alexander E Berezin
Internal Medicine Department, State Medical University, 26, Mayakovsky Av., Zaporozhye, Postcode 69035
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/hm.hm_3_20

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Keywords: Biomarkers, cardiovascular risk, natriuretic peptides, prediabetes, type 2 diabetes mellitus

How to cite this article:
Berezin AE, Berezin AA. Emerging role of natriuretic peptides in diabetes mellitus: New approaches for risk stratification. Heart Mind 2020;4:100-8

How to cite this URL:
Berezin AE, Berezin AA. Emerging role of natriuretic peptides in diabetes mellitus: New approaches for risk stratification. Heart Mind [serial online] 2020 [cited 2022 Dec 4];4:100-8. Available from: http://www.heartmindjournal.org/text.asp?2020/4/4/100/298038

  Introduction Top

Diabetes mellitus (DM) remained the most common metabolic disorder worldwide occupying the 8th leading cause of death.[1] The global statistics of DM yielded about 382 million people had this disease in 2013 and by 2030 the number of diabetics will reach 500 million people.[2] According to the Reduction of Atherothrombosis for Continued Health registry, patients with type 2 DM (T2DM) had a higher risk of cardiovascular (CV) death, nonfatal myocardial infarction, or nonfatal stroke in comparison with the patients without T2DM.[3] Therefore, T2DM was independently associated with a 33% greater risk of hospitalization for heart failure (HF), HF-related outcomes, and CV death.[4],[5] In addition, T2DM and CV diseases frequently coexist and CV risk factors influence significantly on manifestation and progression of both conditions.[6] Although CV factors are affected by some antidiabetic medications, there is not complete correspondence between a control for conventional CV risk factors including glycemic status by lifestyle modification, drug prescription, and diminishing risk of T2DM-related outcomes and CV complications.[7],[8],[9] Moreover, T2DM patients without established CV disease may have even at a greater mortality risk to non-T2DM patients with known CV disease.[9] In this context, advanced risk stratification strategy among the patients with prediabetes and known T2DM requires to be personally modified by used biomarker prediction scores.[10]

Among numerous circulating biomarkers and multiple biomarker-based models reflecting various pathophysiological stages of the development of both T2DM and HF natriuretic peptides (NPs) continue to be a core element in the strategy of CV risk assessment and molecular target for guided therapy of HF.[11] However, serious variability of circulating levels of NPs in the patients with metabolic diseases, including abdominal obesity, metabolic syndrome, and T2DM, requires an adjustment of the diagnostic and predictive cutoff points for NPs, whereas the NPs remain useful biomarker for HF diagnosis and prediction of all-cause mortality, CV death, and HF. The aim of the mini review is to accumulate current knowledge toward controversial prognostic role of circulating NPs in patients with prediabetes and established T2DM.

  Myocardial Biomechanical Stress in Type 2 Diabetes Mellitus Top

Previous magnetic resonance imaging studies have revealed that alterations in glucose metabolism were independently associated with left ventricular (LV) concentric remodeling, less spherical shape, and reduced systolic myocardial shortening in the general population.[12],[13],[14].

[Figure 1] reports the principal molecular mechanisms that correspond to T2DM-induced cardiomyopathy and HF.
Figure 1: Pathophysiological mechanisms of the development of T2DM.induced cardiomyopathy and HF. CV = Cardiovascular, FFA = Free fatty acids, AGEs = Advanced glycation end products, RAGEs = Receptors for advanced glycation end products, GDM = Gestational diabetes mellitus, T2DM = Type 2 diabetes mellitus, CMP = Cardiomyopathy

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However, T2DM-induced cardiomyopathy is heterogenic term that includes several conditions, such as autonomic cardiomyopathy, cardiac hypertrophy, adverse cardiac remodeling, and HF [Figure 2]. At early stage of T2DM-induced cardiomyopathy, isolated diastolic dysfunction and autonomic cardiomyopathy can be determined, whereas at the late stage HFpEF is the most common condition.[12],[13] The speckle-tracking echocardiography studies have yielded that myocardial shortening, LV torsion and myocardial strain was progressively decreased with higher HOMA-IR and torsion was increased only with less severe insulin resistance in individuals with prediabetes.[15],[16] In the coronary artery risk development in young adults study, patients with established T2DM had lowered LV ejection fraction (LVEF), longitudinal systolic strain, and early diastolic strain rate when compared with patients having normal glucose metabolism.[16] The population STAAB cohort study has demonstrated that LV global longitudinal strain and torsion were inversely associated with glycosylated hemoglobin and insulin resistance and that these parameters were found significant lowered in diabetics in compared with nondiabetics without known CV disease.[17]
Figure 2: Types of T2DM-induced cardiomyopathy and key pathophysiological mechanisms. T2DM = Type 2 diabetes mellitus, HFrEF = Heart failure with reduced ejection fraction, HFpEF = Heart failure with preserved ejection fraction

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In fact, glucose abnormalities, lipid toxicity, altered tissue reparation, accelerating atherosclerosis, and coexisting conventional CV risk factors are causes to develop diabetic cardiomyopathy as well as HF related to ischemia causes.[18],[19] In addition, atherosclerosis, systemic and microvascular inflammation, myocardial fibrosis, myocardial infarction, or LV contractile/diastolic dysfunction due to microvascular obstruction are the main causes for myocardial remodeling, for which myocardial biomechanical stress is discussed as crucial pathogenetic mechanism, leading to HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF).[20] Indeed, several molecular mechanisms, such as renin–angiotensin system activation, cardiac autonomic neuropathy, alterations in calcium homeostasis, generation of reactive oxygen or nitrogen species lead to mitochondrial dysfunction, which contributes to ischemic myocardial injury in T2DM. Moreover, mitochondrial dysfunction represents the major cause of death in diabetics regardless of presence of coronary artery disease (CAD) and hypertension.[21] Having evidence that conventional CV risk factors, CAD, and diabetic cardiomyopathy influence negatively on mortality rate and quality-of-life among T2DM patients, there is a suggestion that cardiac biomarkers reflecting various stages of adverse cardiac remodeling and HF advance, such as NPs, would ensure add-on incremental value for the prediction of clinical outcomes (death, major adverse cardiac events [MACEs], hospital admission, and HF-related events) in the patient population. Moreover, the levels of NPs may exhibit personifying predictive information that would be able to yield the greatest predictive potency beyond conventional CV risk factors.[22]

  Natriuretic Peptides: biological Role and Function Top

Biological role of NPs' system as a core element of water and sodium homeostasis is well established and pervasively known.[23] Indeed, predominantly atrial (atrial natriuretic peptide) and brain natriuretic peptide (BNP) and rarely C-type of NP are embedded onto a regulation of cardiorenal homeostasis through appropriate receptor A (NPRA). Clearance of NPs is mediated by their proteolysis by endogenous endopeptidase called neprilysin that activates physiological pathways by which NPs are effectively removed from circulation through receptor-mediated internalization by the NP receptor C (NPRC).[24] In fact, both circulating levels of neprilysin and the NPs' receptors (NPRA and NPRC) ensure the NP bioactivity.[24]

[Table 1] contains data regarding the primary and additional biological function of the NPs.
Table 1: Biological role, function and origin of various natriuretic peptides

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The main triggers for NPs' secretion are myocardial stretching, fluid overload, ischemia/hypoxia, inflammation, and renin–angiotensin–aldosterone system (RAAS).[30] Although system of the NPs is a physiological antagonist of RAAS, there is a wide range of evidence regarding that the NPs through adipose tissue-expressed NPRA and NPRC reciprocally regulate lipolytic activity of adipocytes similar to catecholamine-derived effect that is mediated by the β-adrenergic receptors.[31] In addition, NPs via p38 MAP kinase act as a trigger for overexpression of brown fat genes to increase energy expenditure and regulate adaptive thermogenesis.[32] Therefore, in human cells, including adipocytes, muscle cell, and hepatocytes, NPs promote transcriptional regulation of genes involved in mitochondrial biogenesis, uncoupled respiration (peroxisome proliferator-activated receptor-γ coactivator-1α, and uncoupling protein 1), lipid oxidation, as well as glucose tolerance insulin resistance.[33],[34] Overall, activation of NPRA signaling system in skeletal muscle and hepatocytes is crucial for the maintenance of long-term insulin sensitivity and this phenomenon can link a transformation of prediabetes to T2DM as well as ensures rockets of CV risk.[35],[36] Both C-type of NP and urodilatin provide cardiac and renal protection, reduce blood pressure, induce diuresis, and regulate water and electrolyte homeostasis.[37],[38],[39],[40]

  Circulating Levels and Expression of Receptors for Natriuretic Peptides in Prediabetes and Type 2 Diabetes Mellitus Top

Previous studies have shown that the patients with abdominal obesity, metabolic syndrome, and T2DM had low levels of NPs in comparison with healthy volunteers and that this finding related to increased clearance of NPs. Indeed, NPs are degraded by neprilysin, an activity of which was found to be elevated among the majority of the patients with prediabetes.[41],[42] In addition, insulin may upregulate the NPRC expression in white adipose tissue in obese individuals,[43] while the difference between healthy volunteers and obese patients in the circulating levels of NPs has not been determined by several investigators.[44],[45] Therefore, kidney clearance of NPs was found to be worse in T2DM with nephropathy due to altered glomerular filtration and that was associated with increased circulating levels of BNP and N-terminal prohormone BNP (NT-pro-BNP).[46] However, the reasons for NP level fluctuation in patents with metabolic disease remain uncertain.

Besides being reduced circulating levels of NPRA in obese patients and prediabetics, the expression of the skeletal muscle NPRA is downregulated?.[35] In contrast, it has been found that the number of NP clearance receptors, which are expressed on the surface of the skeletal muscle cells, increased in individuals with either established impaired glucose tolerance or T2DM.[35] Collectively, altered NP receptor/cyclic GMP signaling in skeletal muscle was associated with downregulation of lipid oxidative capacity, increased mitochondrial stress, and increase in IR.[35],[47] Perhaps, NP receptor signaling system is essential for skeletal muscle energy metabolism and downregulation of the NPRA influences muscle weakness and decreased tolerability to physical exercise. Taken together, NP system acts as a powerful endogenous regulator of biomechanical coupling in skeletal muscle mediating glucose tolerance and lipid oxidation and thereby prevents obesity and T2DM. Manifestation of prediabetes often corresponds to NPRA dysfunction and low circulating NP levels in peripheral blood.

  Natriuretic Peptides in Heart Failure Associated with Abnormalities of Glucose Status Top

Current clinical guidelines have been recommended to measure NP levels to diagnose HF when diagnosis is uncertain, to stratify patients from general population into group at higher CV risk and HF manifestation, as well as to prognosticate risks of HF advance and 60-day readmission regardless of the presentation of abdominal obesity, prediabetes, and T2DM.[48],[49] However, asymptomatic patients from general population should have higher circulating levels of NT-proBNP (>300 pg/mL) when compared to individuals having signs and symptoms of HF (125 pg/mL) to be stratified at a risk of death and HF onset.[49] In fact, increased age requires rechecking diagnostic NT-proBNP cutoff point for patients suspecting cardiac dysfunction.[46],[50] Interestingly, among patients without T2DM, elevated levels of NPs yielded greater predictive accuracy for CAD, MACEs, CV mortality, and HF manifestation in comparison with T2DM patients.[48],[50] Although the circulating levels of NT-proBNP did not differ between male and female in general population, elevated NT-proBNP concentrations conferred a higher risk of mortality due to HFpEF in women only, but not in male.[51] However, T2DM patients have demonstrated more pronounced LV hypertrophy and adverse cardiac remodeling, but systolic and diastolic LV function parameters and NT-proBNP serum levels were found to be similar in T2DM and non-T2DM patients.[52] Therefore, serum levels of NPs were found to be independent predictors for atherosclerosis, albuminuria, atrial fibrillation, pulmonary hypertension, and sudden death in patients with abdominal obesity, metabolic syndrome and T2DM, but among patient with HFrEF predictive value of NPs for these outcomes related to the presentation of prediabetes and T2DM.[53],[54],[55],[56] Patients with overweight and abdominal obesity not having T2DM had lower NT-proBNP levels to T2DM patients with and without obesity and higher levels of NT-proBNP to healthy volunteers. In fact, elevated NT-proBNP levels remain a powerful predictive tool to diagnose cardiac abnormalities regardless of glucose status.[57] Moreover, multiple biomarkers' models including NPs occurred to be more prognostically accurate for HF manifestation in non-T2DM patients that in prediabetics with abdominal obesity and T2DM patients.[58],[59]

There are several controversies regarding predictive abilities of elevated levels of NPs in patients with metabolically healthy obesity and metabolic syndrome. First controversy affects evidence of the fact that NPs were not better to conventional cardiac biomarkers, such as cardiac troponins, soluble ST2, ischemia-modified albumin, in prediction of the occurrence of future microvascular and macrovascular complications in obese/ prediabetes patients without known CV disease.[60] In contrast, metabolic biomarkers (adiponectin, resistin, chemerin, and visfatin) sufficiently increased predictive value of NT-proBNP levels for MACEs in patients with various glucose statuses and established HF.[61],[62],[63] The next controversy ties to inverted association between serum levels of NPs (atrial and brain pro-NPs) and the number of components of the metabolic syndrome in young people without established CV disease.[64]

Finally, elevated levels of NT-proBNP remain a strong predictor for CV death among patients with established CV diseases including CAD and HF, even with the confounding effect of prediabetes and T2DM, but cutoff points for serum levels of BNP/NT-proBNP require to be elucidated thoroughly.[65] However, it is still uncertain whether the discriminative potency of NPs for CV death and events in prediabetes and T2DM populations beyond CV disease would be independent from traditional CV risk factors.

  Controversial Prognostication Abilities of Natriuretic Peptides in Clinical Trials among Type 2 Diabetes Mellitus Patients Top

Recently completed EMPEROR-Reduced trial has elucidated that SGLT-2 inhibitor empaglyflosin was better to placebo in improvement of mortality and HF-related clinical outcomes in connection with NT-proBNP dynamics.[73] In the SGLT-2 inhibitor canaglyflosin in the CANVAS trial led to reduce the occurrence of CV death, myocardial infarction, HF, or stroke along with a decrease in serum levels of NT-proBNP when compared to placebo. [Table 2] is summarizes randomized clinical study design, the number of participants, antidiabetic care, CV outcomes, and NP level changes among patients having prediabetes and T2DM.
Table 2: Natriuretic peptide measure I connection with cardiovascular clinical outcomes in prediabetes and type 2 diabetes mellitus patients clinical trials

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The SAIS2 (Sapporo Athero-Incretin Study 2) has revealed that GLP-1 liraglutide and insulin glargine demonstrated similarity in glycemic improvement without changes in NP levels.[66] The T2DM patients with stable CAD and normal values of LVEF who were treated with SGLT-2 inhibitor empagliflozin or placebo were recruited in the EMPA-HEART CardioLink-6.[67],[68] The results of the study have shown that adverse cardiac remodeling was significantly improved by empagliflozin, while circulating levels of NT-proBNP in both patient cohorts were similar. The Empire HF (Empagliflozin in HF Patients With Reduced Ejection Fraction) is now ongoing and the results have not still published.[69]

In contrast, among patients with prediabetes and T2DM without HF serum levels of NT-proBNP remained unaltered regardless of improving glucose homeostasis and decreased CV risk.[77] Interestingly, the change in NT-proBNP serum levels correlated negatively with baseline NT-proBNP levels in T2DM.[78] In addition, in the DEFINE-HF Trial SGLT-2 (sodium-glucose cotransporter 2), inhibitor dapagliflozin did not affect changes in NT-proBNP serum levels, but increased the proportion of patients (as diabetics, as well as nondiabetics) experiencing clinically meaningful improvements in HFrEF-related clinical status.[70] DAPA-HF (dapagliflozin in patients with HF and reduced ejection fraction) trial has yielded a superiority of SGLT2 inhibitor dapagliflozin to placebo in reduction of the MACEs and HF-related outcomes in patients with established HFrEF, but circulating levels of NPs including NT-proBNP were not significantly modified.[71] The authors of the study concluded that the therapy with SGLT-2 inhibitors did not modulate the actions of NP and probably was not associated with decrease in preload and stimulation of diuresis.[71] In contrast, SGLT-1 and -2 inhibitor licogliflozin significantly decreased the levels of NT-proBNP when compared to placebo in patients with T2DM and HFrEF, but there was no sufficient difference between circulating NT-proBNP levels in patients treated with licogliflozin and empagliflozin.[72] Soga et al. reported that SGLT02 inhibitor dapagliflozin influenced positively on adverse cardiac remodeling, but there were no significant changes in BNP over 6-month administration.[79] However, the authors found that the only high concentrations of BNP (≤100 pg/mL) demonstrated a significant decrease over time.[79] Recently completed EMPEROR-Reduced trial has elucidated that SGLT-2 inhibitor empaglyflosin was better to placebo in improvement of mortality and HF-related clinical outcomes in connection with NT-proBNP dynamics.[73] In the SGLT-2 inhibitor canaglyflosin in the CANVAS trial led to reduce the occurrence of CV death, myocardial infarction, HF, or stroke along with a decrease in serum levels of NT-proBNP when compared to placebo.[74] Moreover, this drug was effective in patients with either HFrEF or HFpEF.

It is difficult to speculate a plausible mechanistic reason why GLP-1 analogs and SGLT2 have demonstrated a controversial effect on NP circulating levels in patients with T2DM having HF or no having HF. Perhaps, SGLT-2 inhibitors demonstrated cardiac and kidney protective effects improving metabolic control, oxidative stress, systolic and diastolic functions, and endothelial function, whereas GLP-1 analogs did not have such a variable spectrum of positive impacts on the target organs. As a result of improvement of adverse cardiac remodeling and kidney function, SGLT-2 inhibitors demonstrated an ability to reduce circulating levels of NT-proBNP when they were elevated, while normal and near normal levels of NPs were not modified by these drugs. Thus, high variability of the impact of SGLT-2 inhibitors on NP changes during serial measures may relate to heterogeneity of study patient populations and hyperglycemia controls with antidiabetic drugs. In addition, older people with T2DM at high CV risk treated with SGLT-2 inhibitors during 6 months had lowered levels of NT-proBNP over time, but the signs of decreased preload (tendency to decrease in diameter of the inferior vena cava and intravascular collapse) were not observed.[80] However, the main cause why serum levels of NPs exhibited high variability in numerous clinical trials remained to be uncertain.

Interestingly, dipeptidyl peptidase (DPP)-4 inhibitors had been reported to have neutral effect than deteriorating impact on myocardium in preclinical studies and early large-scale trials.[75],[81],[82] The EXAMINE (Examination of CV Outcomes with Alogliptin versus Standard of Care) trial was included T2DM patients with known CAD treated with DPP-4 inhibitor alogliptin or placebo.[76] The authors found that increase in NT-proBNP plasma levels or persistently high NT-proBNP levels over 6 months were strongly associated with the occurrence of major CV events, whereas low levels of the biomarker accompanied with improved clinical outcomes. However, on the one hand, DPP-4 inhibitors may increase the ability of GLP-1 to stimulate cyclic adenosine monophosphate in cardiac myocytes, and on the other hand, they potentiate the effects of stromal cell-derived factor-1 aggravating cardiac fibrosis and indirectly increase in circulating levels of NPs.[83] Finally, an increased risk of HF progression appeared to be a class effect of DPP-4 inhibitors, even in patients without a history of HF.[84] However, other antidiabetic drugs, i.e., metformin and thiazolidinediones, did not demonstrate predictably clear impact on circulating levels of NPs. Indeed, metformin did not increase the concentration of NPs, but thiazolidinediones through fluid retention acted as triggers for NP level elevation.[69]

  Conclusions Top

NPs are a useful tool for CV risk stratification among patients with prediabetes and T2DM regardless of HF presentation.Occurrence HFrEF / HFpEF in T2DM patients requires the modification of NP cut-off points to establish primary diagnosis of HF and determine HF-related risks. There are several controversies between clinical outcomes and dynamic of circulating levels of NPs in diabetics treated with GLP-1 agonists and SGLT2 inhibitors that needs to be elucidated in large clinical studies in the future.

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  References Top

Tao Z, Shi A, Zhao J. Epidemiological perspectives of diabetes. Cell Biochem Biophys 2015;73:181-5.  Back to cited text no. 1
Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation 2018;137:e67-e492.  Back to cited text no. 2
Cavender MA, Steg PG, Smith SC Jr., Eagle K, Ohman EM, Goto S, et al. Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death: Outcomes at 4 years from the reduction of atherothrombosis for continued health (REACH) Registry. Circulation 2015;132:923-31.  Back to cited text no. 3
Selvin E, Parrinello CM, Sacks DB, Coresh J. Trends in prevalence and control of diabetes in the United States, 1988-1994 and 1999-2010. Ann Intern Med 2014;160:517-25.  Back to cited text no. 4
Bae JC, Cho NH, Suh S, Kim JH, Hur KY, Jin SM, et al. Cardiovascular disease incidence, mortality and case fatality related to diabetes and metabolic syndrome: A community-based prospective study (Ansung-Ansan cohort 2001-12). J Diabetes 2015;7:791-9.  Back to cited text no. 5
Strain WD, Paldánius PM. Diabetes, cardiovascular disease and the microcirculation. Cardiovasc Diabetol 2018;17:57.  Back to cited text no. 6
Alvarez CA, Lingvay I, Vuylsteke V, Koffarnus RL, McGuire DK. Cardiovascular Risk in diabetes mellitus: Complication of the disease or of antihyperglycemic medications. Clin Pharmacol Ther 2015;98:145-61.  Back to cited text no. 7
Yang YS, Yang BR, Kim MS, Hwang Y, Choi SH. Low-density lipoprotein cholesterol goal attainment rates in high-risk patients with cardiovascular diseases and diabetes mellitus in Korea: A retrospective cohort study. Lipids Health Dis 2020;19:5.  Back to cited text no. 8
Balakumar P, Maung-U K, Jagadeesh G. Prevalence and prevention of cardiovascular disease and diabetes mellitus. Pharmacol Res 2016;113:600-9.  Back to cited text no. 9
Berezin AE. Prognostication of clinical outcomes in diabetes mellitus: Emerging role of cardiac biomarkers. Diabetes Metab Syndr 2019;13:995-1003.  Back to cited text no. 10
Berezin AE. Cardiac biomarkers in diabetes mellitus: New dawn for risk stratification? Diabetes Metab Syndr 2017;11 Suppl 1:S201-8.  Back to cited text no. 11
Yoneyama K, Venkatesh BA, Wu CO, Mewton N, Gjesdal O, Kishi S, et al. Diabetes mellitus and insulin resistance associate with left ventricular shape and torsion by cardiovascular magnetic resonance imaging in asymptomatic individuals from the multi-ethnic study of atherosclerosis. J Cardiovasc Magn Reson 2018;20:53.  Back to cited text no. 12
Young AA, Cowan BR. Evaluation of left ventricular torsion by cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2012;14:49.  Back to cited text no. 13
Ilercil A, Devereux RB, Roman MJ, Paranicas M, O'grady MJ, Welty TK, et al. Relationship of impaired glucose tolerance to left ventricular structure and function: The Strong Heart Study. Am Heart J 2001;141:992-8.  Back to cited text no. 14
Lin JL, Sung KT, Su CH, Chou TH, Lo CI, Tsai JP, et al. Cardiac Structural Remodeling, Longitudinal Systolic Strain, and Torsional Mechanics in Lean and Nonlean Dysglycemic Chinese Adults. Circ Cardiovasc Imaging 2018;11:e007047.  Back to cited text no. 15
Kishi S, Gidding SS, Reis JP, Colangelo LA, Venkatesh BA, Armstrong AC, et al. Association of insulin resistance and glycemic metabolic abnormalities with LV structure and function in Middle Age: The CARDIA study. JACC Cardiovasc Imaging 2017;10:105-14.  Back to cited text no. 16
Morbach C, Walter BN, Breunig M, Liu D, Tiffe T, Wagner M, et al. Speckle tracking derived reference values of myocardial deformation and impact of cardiovascular risk factors-Results from the population-based STAAB cohort study. PLoS One 2019;14:e0221888.  Back to cited text no. 17
Shah RV, Abbasi SA, Heydari B, Rickers C, Jacobs DR Jr., Wang L, et al. Insulin resistance, subclinical left ventricular remodeling, and the obesity paradox: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2013;61:1698-706.  Back to cited text no. 18
Turkbey EB, McClelland RL, Kronmal RA, Burke GL, Bild DE, Tracy RP, et al. The impact of obesity on the left ventricle: The multi-Ethnic study of atherosclerosis (MESA). JACC Cardiovasc Imaging 2010;3:266-74.  Back to cited text no. 19
Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 2014;57:660-71.  Back to cited text no. 20
Hölscher ME, Bode C, Bugger H. Diabetic cardiomyopathy: Does the type of diabetes matter? Int J Mol Sci 2016;17(12):2136.  Back to cited text no. 21
Tarquini R, Lazzeri C, Pala L, Rotella CM, Gensini GF. The diabetic cardiomyopathy. Acta Diabetol 2011;48:173-81.  Back to cited text no. 22
Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev 2006;27:47-72.  Back to cited text no. 23
Potter LR, Hunter T. Guanylyl cyclase-linked natriuretic peptide receptors: Structure and regulation. J Biol Chem 2001;276:6057-60.  Back to cited text no. 24
Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol 2016;12:144-53.  Back to cited text no. 25
Verboven K, Hansen D, Jocken JWE, Blaak EE. Natriuretic peptides in the control of lipid metabolism and insulin sensitivity. Obes Rev 2017;18:1243-59.  Back to cited text no. 26
Gupta DK, Wang TJ. Natriuretic peptides and cardiometabolic health. Circ J 2015;79:1647-55.  Back to cited text no. 27
Zois NE, Bartels ED, Hunter I, Kousholt BS, Olsen LH, Goetze JP. Natriuretic peptides in cardiometabolic regulation and disease. Nat Rev Cardiol 2014;11:403-12.  Back to cited text no. 28
Kovacova Z, Tharp WG, Liu D, Wei W, Xie H, Collins S, et al. Adipose tissue natriuretic peptide receptor expression is related to insulin sensitivity in obesity and diabetes. Obesity (Silver Spring) 2016;24:820-8.  Back to cited text no. 29
Moro C. Targeting cardiac natriuretic peptides in the therapy of diabetes and obesity. Expert Opin Ther Targets 2016;20:1445-52.  Back to cited text no. 30
Bordicchia M, Ceresiani M, Pavani M, Minardi D, Polito M, Wabitsch M, et al. Insulin/glucose induces natriuretic peptide clearance receptor in human adipocytes: A metabolic link with the cardiac natriuretic pathway. Am J Physiol Regul Integr Comp Physiol 2016;311:R104-14.  Back to cited text no. 31
Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessì-Fulgheri P, Zhang C, et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest 2012;122:1022-36.  Back to cited text no. 32
Sengenès C, Berlan M, De Glisezinski I, Lafontan M, Galitzky J. Natriuretic peptides: A new lipolytic pathway in human adipocytes. FASEB J 2000;14:1345-51.  Back to cited text no. 33
Engeli S, Birkenfeld AL, Badin PM, Bourlier V, Louche K, Viguerie N, et al. Natriuretic peptides enhance the oxidative capacity of human skeletal muscle. J Clin Invest 2012;122:4675-9.  Back to cited text no. 34
Coué M, Badin PM, Vila IK, Laurens C, Louche K, Marquès MA, et al. Defective natriuretic peptide receptor signaling in skeletal muscle links obesity to type 2 diabetes. Diabetes 2015;64:4033-45.  Back to cited text no. 35
Højlund K. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance. Dan Med J 2014;61:B4890.  Back to cited text no. 36
Moyes AJ, Hobbs AJ. C-type natriuretic peptide: A multifaceted paracrine regulator in the heart and vasculature. Int J Mol Sci 2019;20:2281.  Back to cited text no. 37
Springer J, Azer J, Hua R, Robbins C, Adamczyk A, McBoyle S, et al. The natriuretic peptides BNP and CNP increase heart rate and electrical conduction by stimulating ionic currents in the sinoatrial node and atrial myocardium following activation of guanylyl cyclase-linked natriuretic peptide receptors. J Mol Cell Cardiol 2012;52:1122-34.  Back to cited text no. 38
Fu S, Ping P, Wang F, Luo L. Synthesis, secretion, function, metabolism and application of natriuretic peptides in heart failure. J Biol Eng 2018;12:2.  Back to cited text no. 39
Forssmann W, Meyer M, Forssmann K. The renal urodilatin system: Clinical implications. Cardiovasc Res 2001;51:450-62.  Back to cited text no. 40
Chen Y, Burnett JC Jr., Biochemistry, Therapeutics, and Biomarker Implications of Neprilysin in Cardiorenal Disease. Clin Chem 2017;63:108-15.  Back to cited text no. 41
Lee KM, Lee MC, Lee CJ, Chen YC, Hsu BG. Inverse association of N-terminal Pro?B-type natriuretic peptide level with metabolic syndrome in kidney transplant patients. Transplant Proc 2018;50:2496-501.  Back to cited text no. 42
Pivovarova O, Gogebakan O, Kloting N, Sparwasser A, Weickert MO, Haddad I, et al. Insulin up-regulates natriuretic peptide clearance receptor expression in the subcutaneous fat depot in obese subjects: A missing link between CVD risk and obesity? J Clin Endocrinol Metab 2012;97:E731-9.  Back to cited text no. 43
Sarzani R, Salvi F, Dessi-Fulgheri P, Rappelli A. Renin-angiotensin system, natriuretic peptides, obesity, metabolic syndrome, and hypertension: An integrated view in humans. J Hypertens 2008;26:831-43.  Back to cited text no. 44
Ahued-Ortega JA, León-García PE, Hernández-Pérez E. Correlation of plasma B-type natriuretic peptide levels with metabolic risk markers. Med Clin (Barc) 2018;151:481-6.  Back to cited text no. 45
Di Marca S, Rando A, Cataudella E, Pulvirenti A, Alaimo S, Terranova V, et al. B-type natriuretic peptide may predict prognosis in older adults admitted with a diagnosis other than heart failure. Nutr Metab Cardiovasc Dis 2018;28:636-42.  Back to cited text no. 46
Cleasby ME. ANP-ing Up Diabetes: Impaired natriuretic peptide action in muscle forms a mechanistic link between obesity and diabetes. Diabetes 2015;64:3978-80.  Back to cited text no. 47
Wong YK, Cheung CYY, Tang CS, Hai JSH, Lee CH, Lau KK, et al. High-sensitivity troponin I and B-type natriuretic peptide biomarkers for prediction of cardiovascular events in patients with coronary artery disease with and without diabetes mellitus. Cardiovasc Diabetol 2019;18:171.  Back to cited text no. 48
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129-200.  Back to cited text no. 49
Yancy CW, Jessup M, Bozkurt B, Butler J1, Casey DE Jr., Colvin MM, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2017;136:e137-61.  Back to cited text no. 50
Benomar K, Espiard S, Loyer C, Jannin A, Vantyghem MC. Atrial natriuretic hormones and metabolic syndrome: Recent advances. Presse Med 2018;47:116-24.  Back to cited text no. 51
Palau P, Bertomeu-González V, Sanchis J, Soler M, de la Espriella R, Domínguez E, et al. Differential prognostic impact of type 2 diabetes mellitus in women and men with heart failure with preserved ejection fraction. Rev Esp Cardiol (Engl Ed) 2019. pii: S1885-5857(19) 30264-6.  Back to cited text no. 52
Lindman BR, Dávila-Román VG, Mann DL, McNulty S, Semigran MJ, Lewis GD, et al. Cardiovascular phenotype in HFpEF patients with or without diabetes: A RELAX trial ancillary study. J Am Coll Cardiol 2014;64:541-9.  Back to cited text no. 53
Georgakopoulos C, Vlachopoulos C, Lazaros G, Tousoulis D. Biomarkers of atrial fibrillation in metabolic syndrome. Curr Med Chem 2019;26:898-908.  Back to cited text no. 54
Obaid N, Hadidy SE, Badry ME, Khaled H. The outcome of diabetic patients with cardiomyopathy in critical care unit: Hospital and short-term outcome in a period of six months to one year. Open Access Maced J Med Sci 2019;7:2796-801.  Back to cited text no. 55
Horwich TB, Hamilton MA, Fonarow GC. B-type natriuretic peptide levels in obese patients with advanced heart failure. J Am Coll Cardiol 2006;47:85-90.  Back to cited text no. 56
Krzesinski P, Uzieblo-Zyczkowska B, Gielerak G, Stanczyk A, Piotrowicz K, Piechota W, et al. Echocardiographic assessment and N-terminal pro-brain natriuretic peptide in hypertensives with metabolic syndrome. Adv Clin Exp Med 2017;26:295-301.  Back to cited text no. 57
Mocan M, Anton F, Suciu , Rahaian R, Blaga SN, Farca? AD. Multimarker assessment of diastolic dysfunction in metabolic syndrome patients. Metab Syndr Relat Disord 2017;15:507-14.  Back to cited text no. 58
Prickett TCR, Darlow BA, Troughton RW, Cameron VA, Elliott JM, Martin J, et al. New insights into cardiac and vascular natriuretic peptides: Findings from young adults born with very low birth weight. Clin Chem 2018;64:363-73.  Back to cited text no. 59
Parsanathan R, Jain SK. Novel invasive and noninvasive cardiac-specific biomarkers in obesity and cardiovascular diseases. Metab Syndr Relat Disord 2020;18:10-30.  Back to cited text no. 60
Zhou X, Tao Y, Chen Y, Xu W, Qian Z, Lu X. Serum chemerin as a novel prognostic indicator in chronic heart failure. J Am Heart Assoc 2019;8:e012091.  Back to cited text no. 61
Contaifer D Jr, Buckley LF, Wohlford G, Kumar NG, Morriss JM, Ranasinghe AD, et al. Metabolic modulation predicts heart failure tests performance. PLoS One 2019;14:e0218153.  Back to cited text no. 62
Berezin AE, Samura TA, Kremzer AA, Berezina TA, Martovitskaya YV, Gromenko EA. An association of serum vistafin level and number of circulating endothelial progenitor cells in type 2 diabetes mellitus patients. Diabetes Metab Syndr 2016;10:205-12.  Back to cited text no. 63
Goharian TS, Goetze JP, Faber J, Andersen LB, Grøntved A, Jeppesen JL. Associations of Pro-atrial natriuretic peptide with components of the metabolic syndrome in adolescents and young adults from the general population. Am J Hypertens 2017;30:561-8.  Back to cited text no. 64
Huang FY, Peng Y, Deng XX, Huang BT, Xia TL, Gui YY, et al. The influence of metabolic syndrome and diabetes mellitus on the N-terminal pro-B-type natriuretic peptide level and its prognostic performance in patients with coronary artery disease. Coron Artery Dis 2017;28:159-65.  Back to cited text no. 65
Nomoto H, Miyoshi H, Furumoto T, Oba K, Tsutsui H, Miyoshi A, et al. A comparison of the effects of the GLP-1 analogue liraglutide and insulin glargine on endothelial function and metabolic parameters: A randomized, controlled trial Sapporo Athero-Incretin study 2 (SAIS2). PLoS One 2015;10:e0135854.  Back to cited text no. 66
Verma S, Mazer CD, Yan AT, Mason T, Garg V, Teoh H, et al. Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: The EMPA-HEART cardiolink-6 randomized clinical trial. Circulation 2019;140:1693-702.  Back to cited text no. 67
McMurray JJV, DeMets DL, Inzucchi SE, Køber L, Kosiborod MN, Langkilde AM, et al; DAPA-HF Committees and investigators. A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF). Eur J Heart Fail 2019;21:665-75.  Back to cited text no. 68
Jensen J, Omar M, Kistorp C, Poulsen MK, Tuxen C, Gustafsson I, et al. Empagliflozin in heart failure patients with reduced ejection fraction: A randomized clinical trial (Empire HF). Trials 2019;20:374.  Back to cited text no. 69
Nassif ME, Windsor SL, Tang F, Khariton Y, Husain M, Inzucchi SE, et al. Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: The DEFINE-HF trial. Circulation 2019;140:1463-76.  Back to cited text no. 70
Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RH, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 2019;139:2528-36.  Back to cited text no. 71
de Boer RA, Núñez J, Kozlovski P, Wang Y, Proot P, Keefe D. Effects of the dual sodium-glucose linked transporter inhibitor, licogliflozin vs placebo or empagliflozin in patients with type 2 diabetes and heart failure. Br J Clin Pharmacol 2020;86:1346-56.  Back to cited text no. 72
Packer M, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, et al. Evaluation of the effect of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: Rationale for and design of the EMPEROR-Reduced trial. Eur J Heart Fail 2019;21:1270-8.  Back to cited text no. 73
Figtree GA, Rådholm P, Barrett TB, Perkovic V, Mahaffey KW, de Zeeuw D, et al. Effects of canagliflozin on heart failure outcomes associated with preserved and reduced ejection fraction in type 2 diabetes: Results from the CANVAS program. Circulation. 2019;139:2591-3.  Back to cited text no. 74
Hiemstra JA, Lee DI, Chakir K, Gutiérrez-Aguilar M, Marshall KD, Zgoda PJ, et al. Saxagliptin and tadalafil differentially alter cyclic guanosine monophosphate (cGMP) signaling and left ventricular function in aortic-banded mini-swine. J Am Heart Assoc 2016;5:e003277.  Back to cited text no. 75
Jarolim P, White WB, Cannon CP, Gao Q, Morrow DA. Serial measurement of natriuretic peptides and cardiovascular outcomes in patients with type 2 diabetes in the EXAMINE trial. Diabetes Care 2018;41:1510-5.  Back to cited text no. 76
Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Barsotti E, Clerico A, et al. Renal handling of ketones in response to sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes. Diabetes Care 2017;40:771-6.  Back to cited text no. 77
Cho KY, Nakamura A, Omori K, Takase T, Miya A, Manda N, et al. Effect of switching from pioglitazone to the sodium glucose co-transporter-2 inhibitor dapagliflozin on body weight and metabolism-related factors in patients with type 2 diabetes mellitus: An open-label, prospective, randomized, parallel-group comparison trial. Diabetes Obes Metab 2019;21:710-4.  Back to cited text no. 78
Soga F, Tanaka H, Tatsumi K, Mochizuki Y, Sano H, Toki H, et al. Impact of dapagliflozin on left ventricular diastolic function of patients with type 2 diabetic mellitus with chronic heart failure. Cardiovasc Diabetol 2018;17:132.  Back to cited text no. 79
Kambara T, Shibata R, Osanai H, Nakashima Y, Asano H, Sakai K, et al. Use of sodium-glucose cotransporter 2 inhibitors in older patients with type 2 diabetes mellitus. Geriatr Gerontol Int 2018;18:108-14.  Back to cited text no. 80
Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Heart failure, saxagliptin, and diabetes mellitus: Observations from the SAVOR-TIMI 53 randomized trial. Circulation 2014;130:1579-88.  Back to cited text no. 81
Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: Systematic review and meta-analysis of randomised and observational studies. BMJ 2016;352:i610.  Back to cited text no. 82
Packer M. Worsening heart failure during the use of DPP-4 inhibitors: Pathophysiological mechanisms, clinical risks, and potential influence of concomitant antidiabetic medications. JACC Heart Fail 2018;6:445-51.  Back to cited text no. 83
Kappel BA, Marx N, Federici M. Oral hypoglycemic agents and the heart failure conundrum: Lessons from and for outcome trials. Nutr Metab Cardiovasc Dis 2015;25:697-705.  Back to cited text no. 84


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This article has been cited by
1 Development and Validation of a Nomogram to Predict the 180-Day Readmission Risk for Chronic Heart Failure: A Multicenter Prospective Study
Shanshan Gao,Gang Yin,Qing Xia,Guihai Wu,Jinxiu Zhu,Nan Lu,Jingyi Yan,Xuerui Tan
Frontiers in Cardiovascular Medicine. 2021; 8
[Pubmed] | [DOI]


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