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1.
Front Cardiovasc Med ; 9: 933215, 2022.
Article in English | MEDLINE | ID: mdl-36237903

ABSTRACT

Congestive heart failure (HF) is a complex disease state characterized by impaired ventricular function and insufficient peripheral blood supply. The resultant reduced blood flow characterizing HF promotes activation of neurohormonal systems which leads to fluid retention, often exhibited as pulmonary congestion, peripheral edema, dyspnea, and fatigue. Despite intensive research, the exact mechanisms underlying edema formation in HF are poorly characterized. However, the unique relationship between the heart and the kidneys plays a central role in this phenomenon. Specifically, the interplay between the heart and the kidneys in HF involves multiple interdependent mechanisms, including hemodynamic alterations resulting in insufficient peripheral and renal perfusion which can lead to renal tubule hypoxia. Furthermore, HF is characterized by activation of neurohormonal factors including renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), endothelin-1 (ET-1), and anti-diuretic hormone (ADH) due to reduced cardiac output (CO) and renal perfusion. Persistent activation of these systems results in deleterious effects on both the kidneys and the heart, including sodium and water retention, vasoconstriction, increased central venous pressure (CVP), which is associated with renal venous hypertension/congestion along with increased intra-abdominal pressure (IAP). The latter was shown to reduce renal blood flow (RBF), leading to a decline in the glomerular filtration rate (GFR). Besides the activation of the above-mentioned vasoconstrictor/anti-natriuretic neurohormonal systems, HF is associated with exceptionally elevated levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). However, the supremacy of the deleterious neurohormonal systems over the beneficial natriuretic peptides (NP) in HF is evident by persistent sodium and water retention and cardiac remodeling. Many mechanisms have been suggested to explain this phenomenon which seems to be multifactorial and play a major role in the development of renal hyporesponsiveness to NPs and cardiac remodeling. This review focuses on the mechanisms underlying the development of edema in HF with reduced ejection fraction and refers to the therapeutic maneuvers applied today to overcome abnormal salt/water balance characterizing HF.

2.
ESC Heart Fail ; 9(1): 585-594, 2022 02.
Article in English | MEDLINE | ID: mdl-34821080

ABSTRACT

AIMS: The effect of elevated heart rate (HR) on morbidity and mortality is evident in chronic stable heart failure; data in this regard in acute decompensated heart failure (ADHF) setting are scarce. In this single-centre study, we sought to address the prognostic value of HR and beta-blocker dosage at discharge on all-cause mortality among patients with heart failure and reduced ejection fraction and ADHF. METHODS AND RESULTS: In this retrospective observational study, 2945 patients were admitted for the first time with the primary diagnosis of ADHF between January 2008 and February 2018. Patients were divided by resting HR at discharge into three groups (HR < 70 b.p.m., HR 70-90 b.p.m., and HR > 90 b.p.m.). Evidence-based beta-blockers were defined as metoprolol, bisoprolol, and carvedilol. The doses of prescribed beta-blockers were calculated into a percentage target dose of each beta-blocker and divided to four quartiles: 0 < Dose ≤ 25%, 25% < Dose ≤ 50%, 50% < Dose ≤ 75%, and >75% of the target dose. Cox regression was used to calculate the hazard ratio for various HR categories and adjusting for clinical and laboratory variables. At discharge, 1226 patients had an HR < 70 b.p.m., 1347 patients had an HR at range 70-90 b.p.m., and 372 patients with an HR > 90 b.p.m. The 30 day mortality rate was 2.2%, 3.7%, and 12.1% (P < 0.001), respectively. Concordantly, 1 year mortality rate was 14.6%, 16.7%, and 30.4% (P < 0.001) among patients with HR < 70 b.p.m., HR 70-90 b.p.m., and HR > 90 b.p.m., respectively. The adjusted hazard ratio was significantly increased only in HR above 90 b.p.m. category (hazard ratio, 2.318; 95% confidence interval, 1.794-2.996). CONCLUSIONS: Patients with ADHF and an HR of <90 b.p.m. at discharge had significantly a lower 1 year mortality independent of the dosage of beta-blocker at discharge. It is conceivable to discharge these patients with lower HR.


Subject(s)
Heart Failure , Patient Discharge , Heart Rate/physiology , Humans , Prognosis , Stroke Volume
3.
Front Physiol ; 12: 673497, 2021.
Article in English | MEDLINE | ID: mdl-34733169

ABSTRACT

Congestive heart failure (CHF) often leads to progressive cardiac hypertrophy and salt/water retention. However, its pathogenesis remains largely unclarified. Corin, a cardiac serine protease, is responsible for converting proANP and proBNP to biologically active peptides. Although the involvement of corin in cardiac hypertrophy and heart failure was extensively studied, the alterations in corin and proprotein convertase subtilisin/kexin-6 (PCSK6), a key enzyme in the conversion of procorin to corin, has not been studied simultaneously in the cardiac and renal tissues in cardiorenal syndrome. Thus, this study aims to examine the status of PCSK6/corin in the cardiac and renal tissues of rats with CHF induced by the creation of aorto-caval fistula (ACF). We divided rats with ACF into two subgroups based on the pattern of their urinary sodium excretion, namely, compensated and decompensated. Placement of ACF led to cardiac hypertrophy, pulmonary congestion, and renal dysfunction, which were more profound in the decompensated subgroup. Corin immunoreactive peptides were detected in all heart chambers at the myocyte membranal and cytosolic localization and in the renal tissue, especially in the apical membrane of the proximal tubule, mTAL, and the collecting duct. Interestingly, the expression and abundance of corin in both the cardiac ventricles and renal tissues were significantly increased in compensated animals as compared with the decompensated state. Noteworthy, the abundance of PCSK6 in these tissues followed a similar pattern as corin. In contrast, furin expression was upregulated in the cardiac and renal tissues in correlation with CHF severity. We hypothesize that the obtained upregulation of cardiac and renal PCSK6/corin in rats with compensated CHF may represent a compensatory response aiming at maintaining normal Na+ balance, whereas the decline in these two enzymes may contribute to the pathogenesis of avid sodium retention, cardiac hypertrophy, and blunted atrial natriuretic peptide/brain natriuretic peptide actions in decompensated CHF.

4.
PLoS One ; 16(4): e0239240, 2021.
Article in English | MEDLINE | ID: mdl-33882062

ABSTRACT

Na+/H+ exchangers (NHEs), encoded by Solute Carrier 9A (SLC9A) genes in human, are ubiquitous integral membrane ion transporters that mediate the electroneutral exchange of H+ with Na+ or K+. NHEs, found in the kidney and intestine, play a major role in the process of fluid reabsorption together via Na+,K+-ATPase pump and Na+ channels. Nevertheless, the expression pattern of NHE in the lung and its role in alveolar fluid homeostasis has not been addressed. Therefore, we aimed to examine the expression of NHE specific isoforms in alveolar epithelial cells (AECs), and assess their role in congestive heart failure (CHF). Three NHE isoforms were identified in AEC and A549 cell line, at the level of protein and mRNA; NHE1, NHE2 and mainly NHE8, the latter was shown to be localized in the apical membrane of AEC. Treating A549 cells with angiotensin (Ang) II for 3, 5 and 24 hours displayed a significant reduction in NHE8 protein abundance. Moreover, the abundance of NHE8 protein was downregulated in A549 cells that were treated overnight with Ang II. NHE8 abundance in whole lung lysate was increased in rats with 1-week CHF compared to sham operated rats. However, lower abundance of NHE8 was observed in 4-week CHF group. In conclusion, we herein show for the first time, the expression of a novel NHE isoform in AEC, namely NHE8. Notably, Ang II decreased NHE8 protein levels. Moreover, NHE8 was distinctly affected in CHF rats, probably depending on the severity of the heart failure.


Subject(s)
Alveolar Epithelial Cells/metabolism , Protein Isoforms/metabolism , Sodium-Hydrogen Exchanger 1/metabolism , A549 Cells , Animals , Cell Line, Tumor , Cell Membrane/metabolism , Down-Regulation/physiology , Humans , Intestines/physiology , Kidney/metabolism , Male , Rats , Rats, Sprague-Dawley , Sodium/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism
5.
J Cell Mol Med ; 25(8): 3840-3855, 2021 04.
Article in English | MEDLINE | ID: mdl-33660945

ABSTRACT

Congestive heart failure (CHF) is often associated with kidney and pulmonary dysfunction. Activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid sodium retention, cardiac hypertrophy and oedema formation, including lung congestion. While the status of the classic components of RAAS such as renin, angiotensin converting enzyme (ACE), angiotensin II (Ang II) and angiotensin II receptor AT-1 is well studied in CHF, the expression of angiotensin converting enzyme-2 (ACE2), a key enzyme of angiotensin 1-7 (Ang 1-7) generation in the pulmonary, cardiac and renal systems has not been studied thoroughly in this clinical setting. This issue is of a special interest as Ang 1-7 counterbalance the vasoconstrictory, pro-inflammatory and pro-proliferative actions of Ang II. Furthermore, CHF predisposes to COVID-19 disease severity, while ACE2 also serves as the binding domain of SARS-CoV-2 in human host-cells, and acts in concert with furin, an important enzyme in the synthesis of BNP in CHF, in permeating viral functionality along TMPRSST2. ADAM17 governs ACE2 shedding from cell membranes. Therefore, the present study was designed to investigate the expression of ACE2, furin, TMPRSS2 and ADAM17 in the lung, heart and kidneys of rats with CHF to understand the exaggerated susceptibility of clinical CHF to COVID-19 disease. Heart failure was induced in male Sprague Dawley rats by the creation of a surgical aorto-caval fistula. Sham-operated rats served as controls. One week after surgery, the animals were subdivided into compensated and decompensated CHF according to urinary sodium excretion. Both groups and their controls were sacrificed, and their hearts, lungs and kidneys were harvested for assessment of tissue remodelling and ACE2, furin, TMPRSS2 and ADAM17 immunoreactivity, expression and immunohistochemical staining. ACE2 immunoreactivity and mRNA levels increased in pulmonary, cardiac and renal tissues of compensated, but not in decompensated CHF. Furin immunoreactivity was increased in both compensated and decompensated CHF in the pulmonary, cardiac tissues and renal cortex but not in the medulla. Interestingly, both the expression and abundance of pulmonary, cardiac and renal TMPRSS2 decreased in CHF in correlation with the severity of the disease. Pulmonary, cardiac and renal ADAM17 mRNA levels were also downregulated in decompensated CHF. Circulating furin levels increased in proportion to CHF severity, whereas plasma ACE2 remained unchanged. In summary, ACE2 and furin are overexpressed in the pulmonary, cardiac and renal tissues of compensated and to a lesser extent of decompensated CHF as compared with their sham controls. The increased expression of the ACE2 in heart failure may serve as a compensatory mechanism, counterbalancing the over-activity of the deleterious isoform, ACE. Downregulated ADAM17 might enhance membranal ACE2 in COVID-19 disease, whereas the suppression of TMPRSS2 in CHF argues against its involvement in the exaggerated susceptibility of CHF patients to SARS-CoV2.


Subject(s)
ADAM17 Protein/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Furin/metabolism , Heart Failure/metabolism , Serine Endopeptidases/metabolism , ADAM17 Protein/genetics , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Disease Models, Animal , Gene Expression , Heart Failure/genetics , Humans , Kidney/metabolism , Lung/metabolism , Male , Myocardium/metabolism , Rats, Sprague-Dawley , Renin-Angiotensin System/physiology , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Serine Endopeptidases/genetics
7.
J Am Soc Echocardiogr ; 32(12): 1538-1546.e1, 2019 12.
Article in English | MEDLINE | ID: mdl-31624025

ABSTRACT

BACKGROUND: Significant tricuspid regurgitation (TR) is associated with higher risk for adverse cardiovascular outcomes. Left-sided heart disease (LHD) is a potentially important confounder of this association because it is strongly linked to both TR and clinical outcome. METHODS: We studied 5,886 patients who were followed for a period of 10 years after the index echocardiographic examination. The relationship between TR severity and the end point of admission for heart failure or cardiovascular mortality was analyzed using competing risk analysis, Cox model, and propensity score matching. RESULTS: Higher TR grade was associated with markers of LHD including left ventricular systolic dysfunction, valvular heart disease ≥ moderate, left atrial enlargement, and pulmonary hypertension (all P < .001). There was a significant interaction between TR and the presence of LHD with regard to the end point of heart failure in the competing risks model (P = .01) and the combined end point of heart failure and cardiovascular mortality (P = .02). In both models, moderate/severe TR was associated with higher risk for heart failure (hazard ratio [HR] = 3.10; 95% CI, 1.41-6.84; P = .005) and the combined end point of heart failure or cardiovascular mortality (HR = 2.75; 95% CI, 1.33-5.63, P = .006) only in patients without LHD. Propensity score matching yielded 350 patient pairs, of which 88% had LHD. The HR for heart failure or cardiovascular mortality at 10 years was 0.78 (95% CI, 0.56-1.08; P = .14) in the moderate/severe TR group as compared with the trivial/mild TR. CONCLUSIONS: Moderate or severe functional TR portends an increased risk for heart failure and cardiovascular mortality only when isolated, without concomitant LHD.


Subject(s)
Cause of Death , Heart Failure/mortality , Tricuspid Valve Insufficiency/complications , Tricuspid Valve Insufficiency/diagnostic imaging , Ventricular Dysfunction, Left/mortality , Aged , Cohort Studies , Databases, Factual , Echocardiography, Doppler/methods , Female , Heart Failure/diagnostic imaging , Heart Failure/etiology , Humans , Israel , Kaplan-Meier Estimate , Male , Middle Aged , Prognosis , Propensity Score , Proportional Hazards Models , Retrospective Studies , Risk Assessment , Severity of Illness Index , Survival Analysis , Tricuspid Valve Insufficiency/physiopathology , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/etiology
8.
J Cell Mol Med ; 23(7): 4779-4794, 2019 07.
Article in English | MEDLINE | ID: mdl-31087547

ABSTRACT

The thiazolidinedione (TZD) class of Peroxisome proliferator-activated receptor gamma agonists has restricted clinical use for diabetes mellitus due to fluid retention and potential cardiovascular risks. These side effects are attributed in part to direct salt-retaining effect of TZDs at the renal collecting duct. A recent study from our group revealed that prolonged rosiglitazone (RGZ) treatment caused no Na+/H2 O retention or up-regulation of Na+ transport-linked channels/transporters in experimental congestive heart failure (CHF) induced by surgical aorto-caval fistula (ACF). The present study examines the effects of RGZ on renal and cardiac responses to atrial natriuretic peptide (ANP), Acetylcholine (Ach) and S-Nitroso-N-acetylpenicillamine (SNAP-NO donor). Furthermore, we assessed the impact of RGZ on gene expression related to the ANP signalling pathway in animals with ACF. Rats subjected to ACF (or sham) were treated with either RGZ (30 mg/kg/day) or vehicle for 4 weeks. Cardiac chambers pressures and volumes were assessed invasively via Miller catheter. Kidney excretory and renal hemodynamic in response to ANP, Ach and SNAP were examined. Renal clearance along with cyclic guanosine monophosphate (cGMP), gene expression of renal CHF-related genes and ANP signalling in the kidney were determined. RGZ-treated CHF rats exhibited significant improvement in the natriuretic responses to ANP infusion. This 'sensitization' to ANP was not associated with increases in neither urinary cGMP nor in vitro cGMP production. However, RGZ caused down-regulation of several genes in the renal cortex (Ace, Nos3 and Npr1) and up-regulation of ACE2, Agtrla, Mme and Cftr along down-regulation of Avpr2, Npr1,2, Nos3 and Pde3 in the medulla. In conclusion, CHF+RGZ rats exhibited significant enhancement in the natriuretic responses to ANP infusion, which are known to be blunted in CHF. This 'sensitization' to ANP is independent of cGMP signalling, yet may involve post-cGMP signalling target genes such as ACE2, CFTR and V2 receptor. The possibility that TZD treatment in uncomplicated CHF may be less detrimental than thought before deserves additional investigations.


Subject(s)
Atrial Natriuretic Factor/therapeutic use , Heart Failure/drug therapy , Kidney/pathology , Rosiglitazone/therapeutic use , Acetylcholine/pharmacology , Animals , Atrial Natriuretic Factor/administration & dosage , Blood Pressure/drug effects , Cyclic GMP/metabolism , Endothelium/drug effects , Gene Expression Regulation/drug effects , Heart Failure/pathology , Hemodynamics/drug effects , Kidney/drug effects , Male , Rats, Sprague-Dawley , Rosiglitazone/pharmacology , Signal Transduction/drug effects , Vasodilation/drug effects
9.
J Card Fail ; 25(6): 468-478, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30880249

ABSTRACT

BACKGROUND: Congestive heart failure (CHF) entails a complex interaction between the heart and the kidney that represents a clinical entity called cardiorenal syndrome (CRS). One of the mechanisms underlying CRS includes increased intra-abdominal pressure (IAP). We examined the effect of elevated IAP on kidney function in rats with low- and high-output CHF. METHODS AND RESULTS: Rats with compensated and decompensated CHF induced by means of aortocaval fistula, rats with myocardial infraction (MI) induced by means of left anterior descending artery ligation, and sham control rats were subjected to either 10 or 14 mm Hg IAP. Urine flow (V), Na+ excretion (UNaV), glomerular filtration rate (GFR), and renal plasma flow (RPF) were determined. The effects of pretreatment with tadalafil (10 mg/kg orally for 4 days) on the adverse renal effects of IAP were examined in decompensated CHF and MI. Basal V and GFR were significantly lower in rats with decompensated CHF compared with sham control rats. Decompensated CHF rats and MI rats subjected to 10 and 14 mm Hg IAP exhibited more significant declines in V, UNaV, GFR and RPF than compensated and sham controls. Elevated IAP also induced tubular injury, as evidenced by significantly increased absolute urinary excretion of neutrophil gelatinase-associated lipocalin. In addition, in a nonquantitative histologic analysis, elevated IAP was associated with increase in necrosis and cell shedding to the tubule lumens, especially in the decompensated CHF subgroup. Pretreatment of decompensated CHF rats and MI rats with tadalafil ameliorated the adverse renal effects of high IAP. CONCLUSIONS: Elevated IAP contributes to kidney dysfunction in high- and low-cardiac output CHF. IAP induces both hemodynamic alterations and renal tubular dysfunction. These deleterious effects are potentially reversible and can be ameliorated with the use of phosphodiesterase-5 inhibition.


Subject(s)
Acute Kidney Injury/pathology , Acute Kidney Injury/urine , Disease Models, Animal , Heart Failure/pathology , Heart Failure/urine , Abdominal Cavity/pathology , Acute Kidney Injury/etiology , Animals , Heart Failure/etiology , Lipocalin-2/urine , Pressure/adverse effects , Rats , Rats, Sprague-Dawley
10.
Oncotarget ; 9(31): 21715-21730, 2018 Apr 24.
Article in English | MEDLINE | ID: mdl-29774097

ABSTRACT

Congestive heart failure (CHF) often leads to progressive cardiac hypertrophy and salt/water retention as evident by peripheral and lung edema. Although the pathogenesis of CHF remains largely unclarified, it is widely accepted that neurohormonal changes and inflammatory processes are profoundly involved in structural and functional deterioration of vital organs including, heart, kidney and lungs. Corin, a cardiac serine protease, is responsible for converting pro-ANP and pro-BNP to biologically active natriuretic peptides (NPs). Although the involvement of corin in cardiac hypertrophy and heart failure was extensively studied, the alterations in corin and PCSK6, a key enzyme in the conversion of procorin to corin, have not been studied in the pulmonary tissue. Thus, this study aims at examining the status of PCSK6/Corin in the lung of rats with CHF induced by the creation of aorto-caval fistula (ACF) between the abdominal aorta and vena cava in SD rats. Rats with ACF were divided into 2 subgroups based on the pattern of their daily sodium excretion, compensated and decompensated CHF. Placement of ACF led to cardiac hypertrophy, pulmonary congestion, and renal dysfunction, which were more severe in the decompensated subgroup, despite remarkable elevation of circulatory ANP and BNP levels. Corin mRNA and immunoreactive peptide were detected in pulmonary tissue of all experimental groups. However, the expression and abundance of pulmonary corin significantly increased in the decompensated animals, but not in the compensated ones. Noteworthy, the expression of PCSK6 and ANP/BNP in the pulmonary tissue followed a similar pattern as corin. The upregulation of pulmonary Corin/PCSK6 and NPs were accompanied by local activation of cathepsin L and certain cytokines including IL-6. In light of the anti-inflammatory role of NPs, we postulate that the obtained upregulation of pulmonary PCSK6/Corin along NPs in rats with decompensated CHF may represent a counterbalance response to the inflammatory milieu characterizing CHF especially in severe cases.

11.
Front Immunol ; 8: 716, 2017.
Article in English | MEDLINE | ID: mdl-28674538

ABSTRACT

Congestive heart failure (CHF) has become a major medical problem in the western world with high morbidity and mortality rates. CHF adversely affects several systems, mainly the kidneys and the lungs. While the involvement of the renin-angiotensin-aldosterone system and the sympathetic nervous system in the progression of cardiovascular, pulmonary, and renal dysfunction in experimental and clinical CHF is well established, the importance of pro-inflammatory mediators in the pathogenesis of this clinical setting is still evolving. In this context, CHF is associated with overexpression of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1, and IL-6, which are activated in response to environmental injury. This family of cytokines has been implicated in the deterioration of CHF, where it plays an important role in initiating and integrating homeostatic responses both at the myocardium and circulatory levels. We and others showed that angiotensin II decreased the ability of the lungs to clear edema and enhanced the fibrosis process via phosphorylation of the mitogen-activated protein kinases p38 and p42/44, which are generally involved in cellular responses to pro-inflammatory cytokines. Literature data also indicate the involvement of these effectors in modulating ion channel activity. It has been reported that in heart failure due to mitral stenosis; there were varying degrees of vascular and other associated parenchymal changes such as edema and fibrosis. In this review, we will discuss the effects of cytokines and other inflammatory mediators on the kidneys and the lungs in heart failure; especially their role in renal and alveolar ion channels activity and fluid balance.

12.
Pharmacol Ther ; 168: 75-97, 2016 12.
Article in English | MEDLINE | ID: mdl-27598860

ABSTRACT

The ever-growing global burden of congestive heart failure (CHF) and type 2 diabetes mellitus (T2DM) as well as their co-existence necessitate that anti-diabetic pharmacotherapy will modulate the cardiovascular risk inherent to T2DM while complying with the accompanying restrictions imposed by CHF. The thiazolidinedione (TZD) family of peroxisome proliferator-activated receptor γ (PPARγ) agonists initially provided a promising therapeutic option in T2DM owing to anti-diabetic efficacy combined with pleiotropic beneficial cardiovascular effects. However, the utility of TZDs in T2DM has declined in the past decade, largely due to concomitant adverse effects of fluid retention and edema formation attributed to salt-retaining effects of PPARγ activation on the nephron. Presumably, the latter effects are potentially deleterious in the context of pre-existing fluid retention in CHF. However, despite a considerable body of evidence on mechanisms responsible for TZD-induced fluid retention suggesting that this class of drugs is rightfully prohibited from use in CHF patients, there is a paucity of experimental and clinical studies that investigate the effects of TZDs on salt and water homeostasis in the CHF setting. In an attempt to elucidate whether TZDs actually exacerbate the pre-existing fluid retention in CHF, our review summarizes the pathophysiology of fluid retention in CHF. Moreover, we thoroughly review the available data on TZD-induced fluid retention and proposed mechanisms in animals and patients. Finally, we will present recent studies challenging the common notion that TZDs worsen renal salt and water retention in CHF.


Subject(s)
Heart Failure/etiology , Hypoglycemic Agents/adverse effects , Thiazolidinediones/adverse effects , Animals , Body Fluids/drug effects , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Edema/chemically induced , Heart Failure/physiopathology , Humans , Hypoglycemic Agents/administration & dosage , PPAR gamma/agonists , Risk Factors , Thiazolidinediones/administration & dosage
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