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Cited by 737Cardiac Fibrosis and RemodelingCardiovascular Disease and AdiposityCardiovascular Function and Risk Factors

Cardiac remodeling in obesity

Open access
Abel, E. Dale, Litwin, Sheldon E., Sweeney, Gary·2008·Physiological Reviews
DOI 10.1152/physrev.00017.2007PMC PMC2915933
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Abstract

The dramatic increase in the prevalence of obesity and its strong association with cardiovascular disease have resulted in unprecedented interest in understanding the effects of obesity on the cardiovascular system. A consistent, but puzzling clinical observation is that obesity confers an increased susceptibility to the development of cardiac disease, while at the same time affording protection against subsequent mortality (termed the obesity paradox). In this review we focus on evidence available from human and animal model studies and summarize the ways in which obesity can influence structure and function of the heart. We also review current hypotheses regarding mechanisms linking obesity and various aspects of cardiac remodeling. There is currently great interest in the role of adipokines, factors secreted from adipose tissue, and their role in the numerous cardiovascular complications of obesity. Here we focus on the role of leptin and the emerging promise of adiponectin as a cardioprotective agent. The challenge of understanding the association between obesity and heart failure is complicated by the multifaceted interplay between various hemodynamic, metabolic, and other physiological factors that ultimately impact the myocardium. Furthermore, the end result of obesity-associated changes in the myocardial structure and function may vary at distinct stages in the progression of remodeling, may depend on the individual pathophysiology of heart failure, and may even remain undetected for decades before clinical manifestation. Here we summarize our current knowledge of this complex yet intriguing topic.

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AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes human and animal evidence on how obesity alters cardiac structure and function, emphasizing left ventricular hypertrophy, subclinical systolic/diastolic dysfunction, metabolic and mitochondrial changes, and the obesity paradox. It highlights adipokines—especially leptin and adiponectin—as potential mediators and therapeutic targets.

Key findings

  • Obesity is independently associated with left ventricular hypertrophy, left atrial enlargement, and subclinical impairment of LV systolic and diastolic function; both LV cavity size and wall thickness increase, but wall thickness often increases more, giving a slight predominance of concentric hypertrophy.
  • The obesity paradox is supported by multiple cohorts: among 9,633 consecutive patients undergoing percutaneous coronary interventions, very lean or normal-BMI patients had the highest risk of in-hospital complications, cardiac death, and 1-yr mortality, with mortality progressively decreasing as BMI increased; among 1,676 patients with unstable angina or non-ST-elevation MI treated with early revascularization, obese and very obese patients had less than half the long-term mortality of normal-BMI patients.
  • Proposed mechanisms include altered myocardial substrate utilization (reduced glucose oxidation, increased fatty acid oxidation), mitochondrial dysfunction and uncoupling, impaired insulin signaling, inflammation, pressure/volume overload, sleep apnea, neurohumoral activation, fibrosis, and apoptosis.
  • Adiponectin deficiency enhances progressive cardiac remodeling after aortic constriction, and adiponectin administration diminishes infarct size, apoptosis, and TNF-α production after ischemia-reperfusion; leptin has myriad effects, and the review concludes too much or too little may be detrimental.

Methods

  • Narrative review, not a primary experimental study; no new data are collected.
  • Evidence is drawn from human studies and animal models, including the Framingham Heart Study, clinical cohorts, genetic and diet-induced rodent obesity models, transgenic/knockout mice, isolated perfused hearts, and isolated cardiomyocytes.
  • Main analysis is a qualitative synthesis of structural, functional, metabolic, and adipokine-related mechanisms linking obesity to cardiac remodeling; no meta-analysis or systematic search is described.

Limitations

  • The paper states that human studies mainly rely on cross-sectional data, conclusions are not firm regarding the direct role of obesity in heart failure, heart failure diagnosis is often inaccurate, and obesity frequently coexists with other risk factors such as hypertension, diabetes, and sleep-disordered breathing.
  • The paper states that animal models may not accurately reflect human obesity—for example, leptin deficiency is an extremely rare cause of human obesity—and that cardiac abnormalities in animal studies tend to be more pronounced than in human studies.
  • The paper states that no longitudinal studies in obese subjects are available to delineate the natural history of contractile abnormalities; evident from the text, this is a narrative review without a systematic search or quantitative synthesis.

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Integrity signals

Registry

Crossref · 10.1152/physrev.00017.2007

Cites

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Statistics

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Claims the paper makes

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  • Findingcitation
    § I. Changes in Extracellular Matrix and Fibrosis

    Leptin also increased MMP2 isoform expression and activity in primary human pediatric ventricular myocytes.

    “Leptin also increased MMP2 isoform expression and activity (217).”
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  • Premisecitation
    § C. The Obesity Paradox

    In patients undergoing percutaneous coronary interventions, there was a graded response manifest as a progressive decrease in mortality as BMI increased.

    “Importantly, there was a graded response manifest as a progressive decrease in mortality as BMI increased (121, 123).”
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    • cites [123] Gurm HS, Brennan DM, Booth J, Tcheng JE, Lincoff AM, Topol EJ.Impact of body mass index on outcome after percutaneous coronary intervention (the obesity paradox).Am J Cardiol90: 42–45, 2002. source

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  • Premisecitation
    § C. The Obesity Paradox

    In another cohort of outpatients with established heart failure, higher BMIs were associated with lower mortality risk.

    “In another cohort of outpatients with established heart failure, higher BMIs were associated with lower mortality risk (65).”
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  • Interpretationcitation
    § C. The Obesity Paradox

    Accumulating evidence strongly supports a protective role of obesity once patients have developed cardiovascular disease.

    “Thus, although obesity is widely accepted as a risk factor for coronary heart disease and heart failure, accumulating evidence strongly supports a protective role of obesity once patients have developed cardiovascular disease.”
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  • Premisenone given
    § I. INTRODUCTION

    Abundant evidence shows that obesity is associated with structural and functional changes in the heart in both humans and animal models.

    “Abundant evidence shows that obesity is associated with structural and functional changes in the heart in both humans and animal models (see sects. III and IV).”
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    Findingcitation
    § V. MECHANISMS CONTRIBUTING TO STRUCTURAL AND FUNCTIONAL CHANGES IN THE HEART IN OBESITY

    In ob/ob and db/db mouse hearts prior to the onset of hyperglycemia, reduced glucose oxidation rates and increased FA oxidation rates are present at 4 wk of age.

    “Indeed, reduced glucose oxidation rates and increased FA oxidation rates were present in 4-wk-old obese mice (34).”
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    Findingown data
    § V. MECHANISMS CONTRIBUTING TO STRUCTURAL AND FUNCTIONAL CHANGES IN THE HEART IN OBESITY

    The reduction in glucose oxidation did not decline any further as diabetes developed in these models, although FA oxidation rates increased further.

    “The reduction in glucose oxidation did not decline any further as diabetes developed in these models, although FA oxidation rates increased further.”
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    Findingcitation
    § I. Changes in Extracellular Matrix and Fibrosis

    In primary human pediatric ventricular myocytes, leptin increased pro-collagen type III and type IV mRNA and decreased pro-collagen type I levels but did not change total collagen synthesis.

    “We have recently demonstrated using primary human pediatric ventricular myocytes that leptin increased pro-collagen type III and type IV mRNA and decreased pro-collagen type I levels but did not change total collagen synthesis (217).”
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    Findingcitation
    § VI. ROLE OF ADIPOKINES IN REGULATION OF CARDIAC REMODELING

    In neonatal rat cardiomyocytes, both full-length and globular adiponectin elicited an acute increase in glucose uptake and oxidation; after prolonged treatment, increased fatty acid uptake and oxidation predominated and correlated with decreased PDH activity and glucose oxidation; these effects were mediated via both AdipoR1 and AdipoR2 and occurred via signaling mechanisms involving AMPK, ACC,和A

    “We have recently examined the effect of specific forms of adiponectin on metabolism in neonatal rat cardiomyocytes and found that both full-length and globular adiponectin elicited an acute increase in glucose uptake and oxidation (271). After prolonged treatment, increased fatty acid uptake and oxidation predominated and correlated with decreased PDH activity and glucose oxidation. Collectively,”
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    Premisecitation
    § I. INTRODUCTION

    Central obesity is a risk marker, and probably a risk factor, for the development and progression of coronary artery disease.

    “Indeed, central obesity is undeniably a risk marker, and probably a risk factor for the development and progression of coronary artery disease (43, 105, 185–188, 229, 241, 328).”
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    • cites [186] Kortelainen ML.Association between cardiac pathology and fat tissue distribution in an autopsy series of men without premortem evidence of cardiovascular disease.Int J Obes Relat Metab Disord20: 245–252, 1996.

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    • cites [241] Morricone L, Donati C, Hassan T, Cioffi P, Caviezel F.Relationship of visceral fat distribution to angiographically assessed coronary artery disease: results in subjects with or without diabetes or impaired glucose tolerance.Nutr Metab Cardiovasc Dis12: 275–283, 2002.

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    • cites [328] Sowers JR.Obesity as a cardiovascular risk factor.Am J Med115,Suppl8A: 37S–41S, 2003. source

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    Premisecitation
    § C. The Obesity Paradox

    Overweight and obese individuals are protected from short-term death yet have a long-term mortality risk similar to normal-weight individuals.

    “One recent study has suggested that overweight and obese individuals were in fact protected from short-term death yet have a long-term mortality risk that is similar to normal-weight individuals (254).”
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    Premisecitation
    § I. INTRODUCTION

    Misdiagnosis of heart failure is common and may be more common in obese subjects because of the frequent occurrences of edema and dyspnea.

    “Furthermore, misdiagnosis of heart failure is common and may be more common in obese subjects because of the frequent occurrences of edema and dyspnea (42).”
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    • cites [42] Caruana L, Petrie MC, Davie AP, McMurray JJ.Do patients with suspected heart failure and preserved left ventricular systolic function suffer from “diastolic heart failure” or from misdiagnosis? A prospective descriptive study.Bone Miner J321: 215–218, 2000. source

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    § C. The Obesity Paradox

    Obesity increases the risk of developing heart disease.

    “While it is widely accepted that obesity increases the risk of developing heart disease, a growing number of recent reports document a statistically significant survival benefit in obese patients once they have been diagnosed with cardiovascular diseases (128, 144, 145, 200, 201, 211, 244).”
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    Premisecitation
    § I. INTRODUCTION

    Increased BMI is associated with an increased risk of heart failure in both men and women, and this risk is graded across categories of increasing BMI.

    “The main findings were that increased BMI was associated with an increased risk of heart failure in both men and women and that this risk was graded across categories of increasing BMI.”
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    Premisecitation
    § C. The Obesity Paradox

    The UCP-DTA mouse develops a mild degree of obesity and insulin resistance that is less severe than that observed in mice with mutations in leptin or its receptor.

    “The UCP-DTA mouse in which a diphtheria-toxin transgene is expressed in brown adipose tissue (BAT) resulting in BAT ablation develop a mild degree of obesity and insulin resistance that is less severe than that observed in mice with mutations in leptin or its receptor (215).”
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    Premisecitation
    § C. The Obesity Paradox

    Ob/ob mice on the C57BL6/J background develop obesity, hyperinsulinemia, and impaired glucose tolerance shortly after weaning and develop overt diabetes between 10 and 15 wk of age.

    “Ob/ob mice on the C57BL6/J background develop obesity, hyperinsulinemia, and impaired glucose tolerance shortly after weaning and develop overt diabetes between 10 and 15 wk of age (227).”
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    Premisecitation
    § 2. Patterns of LVH in obesity

    A few studies suggest that LV mass may be increased in obesity, but that the increase is appropriate for body size if obesity is truly uncomplicated.

    “A few studies suggest that LV mass may be increased in obesity, but that the increase is appropriate for body size if obesity is truly “uncomplicated” (i.e., lack of comorbid conditions such as hypertension, diabetes, coronary artery disease, etc.) (151, 155, 156).”
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    § 4. Cardiac adiposity

    Increased epicardial fat is a common finding in severe obesity.

    “Not surprisingly, increased epicardial fat is a common finding in severe obesity.”
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    Premisereasoning
    § 2. Patterns of LVH in obesity

    Wall thickness is commonly increased to a greater extent than cavity size, so there is a slight predominance of concentric cardiac hypertrophy compared with an eccentric pattern.

    “However, wall thickness is commonly increased to a greater extent than cavity size. Thus there appears to be a slight predominance of concentric cardiac hypertrophy (increased wall thickness relative to chamber size) compared with an eccentric pattern of hypertrophy (chamber enlargement is more prominent than the increase in wall thickness).”
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    Premisenone given
    § C. The Obesity Paradox

    Zucker fatty rats are models of obesity, insulin resistance, and glucose intolerance that develop glucose intolerance and relatively mild hyperglycemia as they age.

    “Zucker fatty rats are models of obesity, insulin resistance, and glucose intolerance that develop glucose intolerance and relatively mild hyperglycemia as they age.”
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    Premisecitation
    § C. The Obesity Paradox

    ATGL KO mice develop massive myocardial lipid accumulation presumably because of a defect in lipolysis of myocardial triglyceride leading to contractile dysfunction.

    “Adipose tissue triglyceride lipase (ATGL) KO mice develop massive myocardial lipid accumulation presumably because of a defect in lipolysis of myocardial triglyceride leading to contractile dysfunction.”
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    Premisecitation
    § 4. Cardiac adiposity

    The amount of epicardial fat parallels the amount of visceral adipose tissue and is correlated with the severity of LVH.

    “Iacobellis and colleagues (152, 155) have argued that the amount of epicardial fat parallels the amount of visceral adipose tissue and that the amount of epicardial fat is correlated with the severity of LVH.”
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    Premisecitation
    § 2. Patterns of LVH in obesity

    Both LV cavity size and wall thickness are increased in obese subjects compared with age-matched controls.

    “In addition, the results indicate that both LV cavity size and wall thickness are increased in obese subjects compared with age-matched controls (22, 134, 151, 156, 242, 279, 377).”
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    Premisecitation
    § C. The Obesity Paradox

    Isocaloric high-fat diets that are associated with reduced levels of insulin and leptin appear to attenuate LV hypertrophy in pressure overload hypertrophy and minimize LV remodeling in a rat infarct model.

    “For example, isocaloric high-fat diets that are associated with reduced levels of insulin and leptin appear to attenuate LV hypertrophy in pressure overload hypertrophy and minimize LV remodeling in a rat infarct model (239, 261, 262).”
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    Premisecitation
    § C. The Obesity Paradox

    Diets with increased saturated fat content, or exposure of cultured cells to saturated FA, promote apoptosis, which can be reversed by the addition of mono- or polyunsaturated FA.

    “Studies examining the effects of altering dietary FA composition have suggested that diets with increased saturated fat content, or exposure of cultured cells to saturated FA promote apoptosis, which can be reversed by the addition of mono- or polyunsaturated FA (PUFA) (74, 212, 236, 260).”
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    • cites [74] De Vries JE, Vork MM, Roemen TH, de Jong YF, Cleutjens JP, van der Vusse GJ, van Bilsen M.Saturated but not mono-unsaturated fatty acids induce apoptotic cell death in neonatal rat ventricular myocytes.J Lipid Res38: 1384–1394, 1997. source

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    Premisereasoning
    § C. The Obesity Paradox

    Overexpression of PPAR-α induced lipotoxic cardiomyopathy that was worsened on diets high in long-chain versus medium-chain FAs, implying that lipotoxicity may be mediated primarily by intermediates derived from long-chain FAs.

    “Overexpression of peroxisome proliferator-activated receptor (PPAR)-α induced lipotoxic cardiomyopathy that was worsened on diets that were high in long-chain versus medium-chain FAs, implying that lipotoxicity may be mediated primarily by intermediates derived from long-chain FAs.”
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    Premisecitation
    § 5. Right ventricular size in obesity

    In one study, the majority of obese subjects did not have enough tricuspid valve regurgitation to estimate pulmonary artery pressures, and those that did generally had normal pressures.

    “In fact, in one study the majority of obese subjects did not have enough tricuspid valve regurgitation to even estimate pulmonary artery pressures, and those that did have tricuspid regurgitation generally had normal pressures (378).”
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    § 1. LVH

    Within a given species there are strain differences and age-dependent effects in cardiac hypertrophy.

    “Within a given species there are strain differences and age-dependent effects.”
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    Premisecitation
    § 1. LVH

    Some groups have reported cardiac hypertrophy in hearts of young ob/ob mice, while others have only observed this phenotype in older animals.

    “For example, while some groups have reported cardiac hypertrophy in hearts of young ob/ob mice (30, 34, 227), others have only observed this phenotype in older animals (23, 24).”
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    Premisecitation
    § 4. Cardiac adiposity

    Obese subjects have mild myocyte hypertrophy but no evidence of abnormal collagen accumulation on endomyocardial biopsy.

    “Using a different approach, Kasper et al. (170) performed endomyocardial biopsy to assess myocardial histology, and obese subjects were found to have mild myocyte hypertrophy but no evidence of abnormal collagen accumulation.”
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    Premisecitation
    § 2. Lipid accumulation

    There is no evidence that triglyceride accumulation per se is damaging and it may represent an adaptive mechanism to sequester increased lipids, thereby representing a marker but not necessarily a mediator of lipotoxicity.

    “There is no evidence that triglyceride accumulation per se is damaging and may represent an adaptive mechanism to sequester increased lipids, thereby representing a marker but not necessarily a mediator of lipotoxicity (214).”
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    Premisecitation
    § 4. Cardiac adiposity

    Epicardial fat anterior to the right ventricle is extremely common, and epicardial fat commonly interpolates into the RV free wall.

    “However, widespread use of cardiac MRI and computed tomography, particularly when evaluating for possible arrhythmogenic right ventricular dysplasia, have revealed that epicardial fat anterior to the right ventricle is extremely common (178, 342, 344). Moreover, epicardial fat commonly interpolates into the RV free wall.”
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    Premisecitation
    § 6. Left atrial size in obesity

    Obese subjects in the Framingham heart study had an increased risk of developing atrial fibrillation, and this risk was entirely explained by the increase in LA size.

    “Interestingly, obese subjects in the Framingham heart study were found to have an increased risk of developing atrial fibrillation, and this risk was entirely explained by the increase in LA size (371).”
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    Premisecitation
    § 4. Cardiac adiposity

    Serum markers thought to reflect cardiac collagen turnover are increased in obese subjects.

    “In contrast, Quilliot et al. (288) reported that serum markers thought to reflect cardiac collagen turnover were increased in obese subjects.”
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    Premisecitation
    § 2. Lipid accumulation

    Accumulation of myocardial triglyceride and lipid metabolites such as ceramides is associated with cardiomyocyte apoptosis in Zucker rats, and reduced levels correlate with reduced apoptosis following thiazolidinedione treatment.

    “Accumulation of myocardial triglyceride and lipid metabolites such as ceramides has been associated with cardiomyocyte apoptosis in Zucker rats, and reduced levels correlate with reduced apoptosis following thiazolidinedione (TZD) treatment (394).”
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    Premisecitation
    § 2. LV diastolic function

    E-wave deceleration times have been reported to be increased or unchanged in obese subjects.

    “Similarly, E-wave deceleration times have been reported to be increased (274) or unchanged (279) in obese subjects.”
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    Premisecitation
    § 1. LV systolic function

    Obesity in older individuals appears to pose less of a mortality risk than it does in younger subjects.

    “Lastly, obesity in older individuals appears to pose less of a mortality risk than it does in younger subjects (367).”
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    Premisecitation
    § 1. LV systolic function

    LVH and mild abnormalities of myocardial systolic function have been observed in obese children and adolescents, and the severity of the dysfunction is comparable to that seen in obese subjects in their 30s, 40s, and 50s.

    “Interestingly, LVH and mild abnormalities of myocardial systolic function have been observed in obese children and adolescents (48, 367), and the severity of the dysfunction is comparable to that seen in obese subjects in their 30s, 40s, and 50s.”
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    Premisenone given
    § 1. LV systolic function

    Comorbidities such as hypertension, diabetes, and vascular disease are important causes of LV dysfunction.

    “All of the latter are important causes of LV dysfunction.”
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    Premisecitation
    § 2. LV diastolic function

    Late diastolic (A-wave) velocities have been reported to be increased or unchanged in obese subjects.

    “Lastly, late diastolic (A-wave) velocities have been reported to be increased (28, 155, 242) or unchanged (266, 274, 279, 314).”
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    Interpretationreasoning
    § 3. Fibrosis

    The fibrotic response in obesity is likely due in part to local activation of the renin-angiotensin system, because ACEI or ARB treatment causes regression of fibrosis and normalization of PAI-1 and TGF-β levels.

    “It is likely that the fibrotic response is due in part to local activation of the renin-angiotensin system as treatment of animals with angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) result in regression of fibrosis and normalization of PAI-1 and TGF-β levels.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § 2. LV diastolic function

    Some studies have found reduced early diastolic (E-wave) velocities while others have found them unchanged in obese subjects.

    “Some studies have found reduced early diastolic (E-wave) velocities (155) while others have found them to be unchanged (242, 266, 274, 279, 314).”
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    Interpretationnone given
    § 3. Fibrosis

    Fibrotic responses may also ensue as a result of replacement fibrosis following apoptotic cardiomyocyte death.

    “Fibrotic responses may also ensue as a result of replacement fibrosis following apoptotic cardiomyocyte death.”
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    Interpretationreasoning
    § 1. LV systolic function

    It is unresolved whether long-term obesity leads to heart failure independent of coronary disease or other morbidities.

    “In summary, the jury is still out on whether long-term obesity leads to heart failure independent of coronary disease or other morbidities.”
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    Premisenone given
    § 2. LV diastolic function

    Mitral inflow velocities measured with pulsed-wave Doppler give information about LV relaxation rate and atrial contractile strength, but the effects of altered loading conditions (i.e., LA pressure) tend to dominate over the effects of LV relaxation abnormalities.

    “Mitral inflow velocities measured with pulsed-wave Doppler give information about LV relaxation rate and atrial contractile strength, but the effects of altered loading conditions (i.e., LA pressure) tend to dominate over the effects of LV relaxation abnormalities.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § 3. Fibrosis

    The fibrosis in obese animal hearts is correlated with increased expression of PAI-1, increased levels of TGF-β, and increased activation of stress signaling pathways such as JNK.

    “The fibrosis is correlated with increased expression of plasminogen activator inhibitor 1 (PAI-1), increased levels of transforming growth factor (TGF)-β, and increased activation of stress signaling pathways such as Jun NH2-terminal kinase (JNK).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 1. In vivo studies

    In ob/ob and db/db mice, LV function differs by strain and varies with age.

    “In a study of ob/ob and db/db mice in which cardiac function was evaluated using invasive LV catheterization, Buchanan et al. (34) reported that LV function differed by strain and varied with age.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] source

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  • May combine two claims.

    Interpretationreasoning
    § 1. In vivo studies

    These data are consistent with a progressive reduction in cardiac function, which may represent the cumulative effects of persistent hyperglycemia, insulin resistance, and increased myocardial lipid supply.

    “These data are consistent with a progressive reduction in cardiac function, which may represent the cumulative effects of persistent hyperglycemia, insulin resistance, and increased myocardial lipid supply.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § 2. LV diastolic function

    The exaggerated rise in wedge pressure in obese subjects indicates reduced distensibility of the central circulation.

    “These data were interpreted as showing reduced distensibility of the central circulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 1. In vivo studies

    In 15-wk-old ob/ob mice, the increase in dP/dt remains and LV end-diastolic pressure does not increase.

    “In 15-wk-old ob/ob mice, the increase in dP/dt remained and LV end-diastolic pressure did not increase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 1. In vivo studies

    In 10- to 11-wk-old female ob/ob mice, there are minimal changes in LV systolic function under baseline conditions but a reduction in the inotropic response to dobutamine, and evidence of diastolic dysfunction manifested by reduced E/A ratios.

    “In 10- to 11-wk-old female ob/ob mice, Christoffersen et al. (53) reported minimal changes in LV systolic function under baseline conditions but a reduction in the inotropic response to dobutamine. They reported evidence of diastolic dysfunction manifested by reduced E/A ratios (53).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given
    § 4. Vascular function

    Both macro- and microvascular abnormalities likely contribute to the many structural and functional problems of the heart in obesity.

    “Both macro- and microvascular abnormalities likely contribute to the many structural and functional problems of the heart in obesity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § 2. LV diastolic function

    Increased age is associated with reduced E-velocity, prolonged E-deceleration time, and increased A-velocity.

    “Because increased age predictably is associated with reduced E-velocity, prolonged E-deceleration time, and increased A-velocity, controlling for age is mandatory in the assessment of mitral flow patterns.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 1. In vivo studies

    UCP-DTA mice have a modest increase in blood pressure, eccentric LVH (with increased LV chamber size), and increased cardiac output.

    “These mice have a modest increase in blood pressure, eccentric LVH (with increased LV chamber size), and increased cardiac output (54).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § 2. LV diastolic function

    Decreases in early diastolic tissue velocities and diastolic strain rate predominantly reflect slowing in the rate of LV relaxation.

    “It is believed that decreases in these parameters predominantly reflect slowing in the rate of LV relaxation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 1. In vivo studies

    In younger ob/ob and db/db mice (4-5 wk of age), rates of LV contraction and relaxation (dP/dt) are increased despite significant obesity, and LV systolic pressures are increased without significant differences in LV end-diastolic pressures.

    “In younger mice of both strains, rates of LV contraction and relaxation (dP/dt) were actually increased in young animals (4–5 wk of age) despite the presence of significant obesity. Moreover, LV systolic pressures were increased, without any significant differences in LV end-diastolic pressures.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 1. In vivo studies

    Caloric restriction in ob/ob mice on the LDLR null background leads to a 45% reduction in body weight, reduced atherosclerosis, improved glucose homeostasis, reduced markers of inflammation, and normalization of cardiac function.

    “Caloric restriction leads to a 45% reduction in body weight, reduced atherosclerosis, improved glucose homeostasis, reduced markers of inflammation, and normalization of cardiac function (361).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [361] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § 4. Vascular function

    It is nearly impossible to dissect out the independent contributions of the different components of the metabolic syndrome because abdominal obesity is part of its diagnostic criteria.

    “However, since abdominal obesity is part of the diagnostic criteria for the metabolic syndrome, it is nearly impossible to dissect out the independent contributions of the different components of this syndrome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 3. RV function

    In obese patients, these RV changes were associated with reduced exercise capacity but not the duration of obesity or the severity of sleep apnea.

    “In obese patients, these changes were associated with reduced exercise capacity but not the duration of obesity or the severity of sleep apnea.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 4. Vascular function

    Obesity, especially abdominal obesity, is a well-defined risk factor for the development of atherosclerotic coronary artery disease.

    “Suffice it to say that obesity, especially abdominal obesity, is a well-defined risk factor for the development of atherosclerotic coronary artery disease (12, 188, 241).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12] source

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    • cites [188] source

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    • cites [241] Morricone L, Donati C, Hassan T, Cioffi P, Caviezel F.Relationship of visceral fat distribution to angiographically assessed coronary artery disease: results in subjects with or without diabetes or impaired glucose tolerance.Nutr Metab Cardiovasc Dis12: 275–283, 2002.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. In vivo studies

    In db/db mice, systolic and diastolic dysfunction by echocardiography is absent at 6 wk of age but present at 12 wk of age.

    “Similar findings have been reported in db/db mice with evidence of systolic and diastolic function by echocardiography that was absent in 6-wk-old (shortly after onset of hyperglycemia) but present in 12-wk-old mice (313).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [313] source

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  • May combine two claims.

    Premisecitation
    § 1. In vivo studies

    In genetically obese Zucker fatty rats, LVH is present in young animals shortly after the development of diabetes, associated with increased LV function by echocardiography; they eventually develop significant LV dysfunction in vivo as evidenced by decreased fractional shortening, which can be reversed with TZD treatment.

    “In genetically obese Zucker fatty rats, LVH is present in young animals shortly after the development of diabetes. This is associated with increased LV function by echocardiography (104); however, they eventually develop significant LV dysfunction in vivo as evidenced by decreased fractional shortening. This can be reversed with TZD treatment (394).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [104] source

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    • cites [394] source

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  • May combine two claims.

    Premisenone given
    § 2. LV diastolic function

    Elevated levels of BNP are indicative of volume overload and higher LV filling pressures.

    “Elevated levels of this hormone are indicative of volume overload and higher LV filling pressures.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § 4. Normoxia versus ischemia

    Earliest changes are seen in isolated perfused hearts and precede detectable changes in vivo.

    “Earliest changes are seen in isolated perfused hearts and precede detectable changes in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § C. Comparison Between Animal and Human Data

    Leptin therapy has been associated with marked reversal of the obesity phenotype in ob/ob mice, whereas administration of leptin has been largely ineffective in treating human obesity.

    “To further emphasize this point, leptin therapy has been associated with marked reversal of the obesity phenotype in ob/ob mice, whereas administration of leptin has unfortunately been largely ineffective in treating human obesity (27).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] source

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  • May combine two claims.

    Premisecitation
    § 2. Studies in isolated hearts

    In Langendorff-perfused hearts from fa/fa (Zucker) rats prior to the onset of diabetes, cardiac function is depressed; after the onset of diabetes, increased FA utilization and decreased glucose and lactate utilization are observed.

    “In Langendorff-perfused hearts from fa/fa (Zucker) rats prior to the onset of diabetes, cardiac function was also depressed (369), and in rats studied after the onset of diabetes, increased FA utilization and decreased glucose and lactate utilization were observed (370).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [369] source

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    • cites [370] source

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  • May combine two claims.

    Premisecitation
    § 3. Studies in isolated cardiomyocytes or papillary muscles

    In ob/ob mice, cardiomyocyte contractile function is reduced and is associated with reduced calcium sensitivity and altered calcium transients.

    “In ob/ob mice, cardiomyocyte contractile function is reduced and is associated with reduced calcium sensitivity and altered calcium transients (88, 207).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [88] source

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    • cites [207] source

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  • May combine two claims.

    Premisecitation
    § 4. Normoxia versus ischemia

    Leptin administration has been shown to reduce infarct size and enhance myocardial functional recovery following coronary artery ligation in mice.

    “Thus leptin administration has been shown to reduce infarct size and enhance myocardial functional recovery following coronary artery ligation in mice (4, 326).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] source

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    • cites [326] source

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    Premisecitation
    § 2. Studies in isolated hearts

    In isovolumic ob/ob hearts, cardiac performance is similar at low work loads but significantly reduced at increased work loads.

    “In isovolumic ob/ob hearts, although cardiac performance was similar at low work loads, there was a significant reduction at increased work loads (30).”
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    • cites [30] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § C. Comparison Between Animal and Human Data

    The wealth of data that can be derived from animal studies allows for "proof of concept" experiments that are often impossible to perform in humans.

    “Despite these caveats, the wealth of data that can be derived from animal studies allows for “proof of concept” experiments that are often impossible to perform in humans.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 4. Normoxia versus ischemia

    Treatment with PPAR-γ or PPAR-α agonists while improving myocardial substrate utilization did not increase postischemic recovery in db/db hearts, but acute treatment with high concentrations of glucose and insulin increased postischemic recovery and cardiac efficiency.

    “Treatment with PPAR-γ or PPAR-α agonists while improving myocardial substrate utilization did not increase postischemic recovery in db/db hearts (3, 36), but acute treatment with high concentrations of glucose and insulin, which substantially increased glucose oxidation rates, increased postischemic recovery and cardiac efficiency (90).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] source

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    • cites [36] source

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    • cites [90] source

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  • May combine two claims.

    Premisenone given
    § C. Comparison Between Animal and Human Data

    Leptin deficiency or absence of functional leptin receptors is the basis of obesity in the widely studied ob/ob and db/db mice, whereas leptin deficiency is an extremely rare cause of obesity in humans.

    “For example, leptin deficiency or absence of functional leptin receptors is the basis of obesity in the widely studied ob/ob and db/db mice, whereas leptin deficiency is an extremely rare cause of obesity in humans.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § C. Comparison Between Animal and Human Data

    The environmental impact on heart failure in humans is another factor that is difficult to mimic in laboratory animals.

    “The environmental impact on heart failure in humans is another factor that is difficult to mimic in laboratory animals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 4. Normoxia versus ischemia

    Studies in nondiabetic rats have shown a positive benefit of TZD treatment upon ischemia/reperfusion, although this has not been shown to be true for other models such as pigs.

    “Studies in nondiabetic rats have also shown a positive benefit of TZD treatment upon ischemia/reperfusion (158, 176, 390), although this has not been shown to be true for other models such as pigs (380).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [158] source

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    • cites [176] source

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    • cites [390] source

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    • cites [380] source

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  • May combine two claims.

    Premisecitation
    § 1. In vivo studies

    Twelve weeks of high-fat feeding of Sprague-Dawley rats revealed no changes in invasive LV hemodynamics, echocardiographic parameters, LV hypertrophy, or LV fibrosis despite significant obesity and dyslipidemia.

    “Thus 12 wk of high-fat feeding of Sprague-Dawley rats revealed no changes in invasive LV hemodynamics, e.g., dP/dt, echocardiographic parameters, LV hypertrophy, or LV fibrosis despite significant obesity and dyslipidemia (40).”
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    • cites [40] source

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    Premisecitation
    § 4. Normoxia versus ischemia

    In fa/fa rats studied very shortly after the onset of hyperglycemia, ischemia was associated with increased ischemic contracture, but functional recovery following reperfusion was enhanced despite reduced baseline cardiac function.

    “In fa/fa rats studied very shortly after the onset of hyperglycemia, ischemia was associated with increased ischemic contracture, but functional recovery following reperfusion was enhanced in the obese mice despite the fact that at baseline, cardiac function was reduced (369).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [369] source

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  • May combine two claims.

    Premisecitation
    § 3. Studies in isolated cardiomyocytes or papillary muscles

    Treatment of Wistar rats with a high-fat diet for 7 wk was associated with LV hypertrophy, triglyceride accumulation, and insulin resistance; papillary muscles revealed an increase in baseline and maximal force generation, but impaired recovery from high work loads, impaired insulin-mediated augmentation of calcium-mediated contractility, and reduced insulin-mediated phosphorylation of phospholamb

    “Treatment of Wistar rats with a high-fat diet for 7 wk was associated with LV hypertrophy triglyceride accumulation and insulin resistance. Papillary muscles revealed an increase in baseline and maximal force generation, but impaired recovery from high work loads, impaired insulin-mediated augmentation of calcium-mediated contractility, and reduced insulin-mediated phosphorylation of phospholamban”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [269] source

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  • May combine two claims.

    Premisecitation
    § 2. Studies in isolated hearts

    Treatment of Zucker rats with a TZD improved systemic glucose homeostasis and intracardiac triglyceride accumulation, increased glucose oxidation rates, and improved cardiac function.

    “Treatment of Zucker rats with a TZD improved systemic glucose homeostasis and intracardiac triglyceride accumulation, increased glucose oxidation rates, and improved cardiac function (115).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] source

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  • May combine two claims.

    Interpretationreasoning
    § 4. Normoxia versus ischemia

    The extent of dysfunction in vivo or in vitro becomes more evident as the duration of the obesity increases, or following an ischemic insult.

    “The extent of dysfunction in vivo or in vitro becomes more evident as the duration of the obesity increases, or following an ischemic insult.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given
    § C. Comparison Between Animal and Human Data

    End-organ effects of obesity that require a long duration to become evident are much easier to study and observe in small rodents with a life span of 1-2 years than in humans with a much longer life span.

    “Lastly, end-organ effects of obesity that require a long duration to become evident are much easier to study and observe in small rodents with a life span of 1–2 years than in humans with a much longer life span.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 4. Normoxia versus ischemia

    Studies in older Zucker rats demonstrated reduced recovery from ischemia, which could be prevented by treating these animals with a TZD.

    “In contrast, studies in older Zucker rats demonstrated reduced recovery from ischemia, which could be prevented by treating these animals with a TZD (159, 322, 389).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [159] source

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    • cites [322] source

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    • cites [389] source

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  • May combine two claims.

    Premisecitation
    § 4. Normoxia versus ischemia

    Infarct size is unchanged in high-fat fed models but increased in db/db mice.

    “Infarct size is unchanged in high-fat fed models (347) but increased in db/db mice (160).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [347] source

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    • cites [160] source

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  • May combine two claims.

    Premisecitation
    § 2. Studies in isolated hearts

    Treatment of db/db mice with PPAR-γ or PPAR-α agonists can improve cardiac metabolism, but do not necessarily restore cardiac function.

    “Similar studies in db/db mice revealed that treatment of these mice with PPAR-γ or PPAR-α agonists can improve cardiac metabolism, but do not necessarily restore cardiac function (1, 2, 36).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] source

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    • cites [2] source

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    • cites [36] source

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  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning
    § C. Comparison Between Animal and Human Data

    The two lines of investigation are felt to be synergistic, even though establishing disease pathogenesis and final proof of the therapeutic benefits of any treatment must ultimately be obtained in clinical studies.

    “Thus the two lines of investigation are felt to be synergistic, even though establishing disease pathogenesis and final proof of the therapeutic benefits of any treatment must ultimately be obtained in clinical studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 4. Normoxia versus ischemia

    Isolated working hearts from db/db mice exhibit reduced recovery following ischemia and reperfusion after diabetes develops, but recovery is normal in the pre-diabetic stage.

    “Thus isolated working hearts from db/db mice exhibit reduced recovery following ischemia and reperfusion after diabetes develops, but recovery is normal in the pre-diabetic stage (3).”
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    • cites [3] source

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  • May combine two claims.

    Premisecitation
    § C. Impaired Insulin Signaling

    An inflammatory state is both a causative factor in inducing MI and a primary constituent of the response to MI.

    “and an inflammatory state is both a causative factor in inducing MI and a primary constituent of the response to MI (210, 341, 385).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [210] source

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    • cites [341] source

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    • cites [385] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § C. Impaired Insulin Signaling

    Several studies have established clear correlations between markers of inflammation and mortality in patients with heart failure.

    “Several studies have established clear correlations between markers of inflammation and mortality in patients with heart failure (157, 246).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [157] source

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    • cites [246] source

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    Premisecitation
    § C. Impaired Insulin Signaling

    Although some studies have failed to show a relationship between sleep apnea and LV hypertrophy, the majority do support such an association.

    “Although some studies have failed to show a relationship between sleep apnea and LV hypertrophy, the majority do support such an association (18, 22, 69, 250, 256–258, 284, 287, 331, 373).”
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    • cites [18] source

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    • cites [22] source

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    • cites [69] source

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    • cites [250] source

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    • cites [256] source

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    • cites [257] source

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    • cites [258] source

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    • cites [284] source

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    • cites [287] source

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    • cites [331] source

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  • May combine two claims.

    Premisecitation
    § C. Impaired Insulin Signaling

    A disparity in the inflammatory cytokine system occurs in obese individuals with heart failure: pro-inflammatory cytokines IL-6, IL-1β, ANP, and TNF-α increase, while anti-inflammatory cytokines IL-10 and TGF-β do not correspondingly increase.

    “It appears that a disparity in the inflammatory cytokine system occurs in obese individuals with heart failure since, while pro-inflammatory cytokines such as interleukin (IL)-6, IL-1β, atrial natriuretic peptide (ANP), and tumor necrosis factor (TNF)-α increase, there is not a corresponding increase in anti-inflammatory cytokines such as IL-10 and TGF-β (122, 366).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [122] source

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    • cites [366] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § C. Impaired Insulin Signaling

    In cardiomyocytes, AGEs regulate the response to ischemia-reperfusion injury via modulation of cardiac energy metabolism.

    “Furthermore, it has been suggested that in cardiomyocytes AGEs regulate the response to ischemia-reperfusion injury via modulation of cardiac energy metabolism (33).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] source

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    Premisecitation
    § C. Impaired Insulin Signaling

    Stroke volume and cardiac output are both increased in obese individuals.

    “In addition, stroke volume and cardiac output are both increased (13, 49, 165, 170, 284).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [13] source

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    • cites [49] Chinali M, Devereux RB, Howard BV, Roman MJ, Bella JN, Liu JE, Resnick HE, Lee ET, Best LG, de Simone G.Comparison of cardiac structure and function in American Indians with and without the metabolic syndrome (the Strong Heart Study).Am J Cardiol93: 40–44, 2004. source

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    • cites [165] source

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    • cites [170] source

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    • cites [284] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § C. Impaired Insulin Signaling

    C-reactive protein may serve as a useful prognostic tool and as a marker of long-term mortality in patients with acute MI.

    “C-reactive protein, a heavily studied serum marker of inflammation, may serve as a useful prognostic tool and as a marker of long-term mortality in patients with acute MI (329, 332).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [329] source

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    • cites [332] source

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    Premisecitation
    § C. Impaired Insulin Signaling

    There are multiple routes by which sleep apnea could lead to LV hypertrophy, including exacerbation of nighttime and daytime hypertension, increased sympathetic tone, chronic hypoxemia, and exaggerated swings in intrathoracic pressure during obstructive episodes.

    “There are multiple routes by which sleep apnea could lead to LV hypertrophy, including exacerbation of nighttime and daytime hypertension, increased sympathetic tone, chronic hypoxemia, and exaggerated swings in intrathoracic pressure during obstructive episodes (287).”
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    • cites [287] source

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    Premisecitation
    § C. Impaired Insulin Signaling

    A 12-wk high-fat diet in rats induced obesity and elevated serum AGE levels which correlated with increased O-Glc-NAc modifications and apoptosis in cardiomyocytes, similar to apoptosis induced by hyperglycemia.

    “Ren’s group recently demonstrated that a 12-wk high-fat diet in rats induced obesity and elevated serum AGE levels which correlated with increased O-Glc-NAc modifications and apoptosis in cardiomyocytes (205) in a similar manner to the apoptosis induced by hyperglycemia (206).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [205] source

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    • cites [206] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § C. Impaired Insulin Signaling

    Pressure overload typically causes a concentric pattern of hypertrophy.

    “Typically, we think of pressure overload as causing a concentric pattern of hypertrophy (120).”
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    • cites [120] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § C. Impaired Insulin Signaling

    Chronic volume overload or high output failure is classically felt to produce an eccentric form of cardiac hypertrophy with enlarged cardiac chambers, but normal wall thickness.

    “Chronic volume overload or high output failure is classically felt to produce an eccentric form of cardiac hypertrophy with enlarged cardiac chambers, but normal wall thickness (120).”
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    • cites [120] source

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  • May combine two claims.

    Premisecitation
    § I. Changes in Extracellular Matrix and Fibrosis

    Studies in Zucker fatty rats have shown increased apoptosis that was associated with increased cardiomyocyte levels of ceramide and triglycerides; treatment with a TZD reduced triglyceride and ceramide levels and reduced apoptosis.

    “Studies in Zucker fatty rats have shown increased apoptosis that was associated with increased cardiomyocyte levels of ceramide and triglycerides. Treatment of these mice with a TZD reduced triglyceride and ceramide levels and reduced apoptosis (394).”
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    • cites [394] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § I. Changes in Extracellular Matrix and Fibrosis

    Myocyte apoptosis has been suggested to be an important etiological component of heart failure, particularly in the transition from compensatory remodeling to heart failure, although this concept has been somewhat contentious.

    “Myocyte apoptosis has been suggested to be an important etiological component of heart failure, particularly in the transition from compensatory remodeling to heart failure (112), although this concept has been somewhat contentious (95, 189, 295, 301).”
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    • cites [112] source

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    • cites [95] source

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    • cites [189] source

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    • cites [295] source

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    • cites [301] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § I. Changes in Extracellular Matrix and Fibrosis

    Elevated matrix metalloproteinase (MMP)-9 activity in the left ventricle of the human heart appears to be an early trigger of pathological remodeling leading to end-stage human heart failure.

    “Although relatively little is known to date, Tyagi’s group (243) has suggested that elevated matrix metalloproteinase (MMP)-9 activity in the left ventricle of the human heart appears to be an early trigger of pathological remodeling leading to end-stage human heart failure.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [243] source

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  • May combine two claims.

    Interpretationreasoning
    § C. Impaired Insulin Signaling

    The sympathetic and renin-angiotensin pathways are interrelated and are both prohypertrophic via direct signaling effects and hemodynamic effects.

    “These two pathways are interrelated and are both prohypertrophic via direct signaling effects and hemodynamic effects (i.e., vasoconstriction and elevation of blood pressure).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § I. Changes in Extracellular Matrix and Fibrosis

    Inhibiting caspases can both reduce the occurrence of heart failure or slow its progression after MI as well as improve contractile function.

    “Accordingly, inhibiting caspases can both reduce the occurrence of heart failure or slow its progression after MI (45, 131, 374, 383, 384) as well as improve contractile function (45).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [45] source

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    • cites [131] source

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    • cites [374] source

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    • cites [383] source

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    • cites [384] source

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  • May combine two claims.

    Premisecitation
    § C. Impaired Insulin Signaling

    In that study, a diagnosis of hypertension or an average nocturnal O2 saturation <85% each had synergistic interactions with increasing BMI.

    “In this study, a diagnosis of hypertension or an average nocturnal O2 saturation <85% each had synergistic interactions with increasing BMI.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] source

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  • May combine two claims.

    Premisecitation
    § I. Changes in Extracellular Matrix and Fibrosis

    Endomyocardial biopsies from patients with dilated or ischemic cardiomyopathy and end-stage heart failure demonstrated apoptotic cardiomyocyte death, and there was increased susceptibility to hypoxia-induced apoptosis in cardiomyocytes isolated from failing human hearts.

    “Endomyocardial biopsies from patients with dilated or ischemic cardiomyopathy and end-stage heart failure demonstrated apoptotic cardiomyocyte death (253, 263), and there was increased susceptibility to hypoxia-induced apoptosis in cardiomyocytes isolated from failing human hearts (351).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [253] source

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    • cites [263] source

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    • cites [351] source

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  • Classified as probably not a substantial claim.

    Premisecitation
    § C. Impaired Insulin Signaling

    Adipose tissue contains the major components of a local renin-angiotensin system.

    “Engeli et al. have suggested that adipose tissue contains the major components of a local renin-angiotensin system (96).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] source

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  • May combine two claims.

    Premisecitation
    § I. Changes in Extracellular Matrix and Fibrosis

    Increased fibrosis in coronary vessels as well as accumulation of collagen in the cardiac interstitium was detected in a high-fat diet-induced rabbit model of obesity.

    “Increased fibrosis in coronary vessels as well as accumulation of collagen in the cardiac interstitium was detected in a high-fat diet-induced rabbit model of obesity (39).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] source

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  • May combine two claims.

    Premisecitation
    § VI. ROLE OF ADIPOKINES IN REGULATION OF CARDIAC REMODELING

    In a high-fat feeding regimen in mice, obesity-associated defects in cardiac function did not develop in concert with insulin resistance, and changes in circulating adipokines could be an important contributing factor in cardiac dysfunction.

    “This was addressed by Kim’s group via a high-fat feeding regimen in mice (273). They found that obesity-associated defects in cardiac function did not develop in concert with insulin resistance and concluded that changes in circulating adipokines could be an important contributing factor in cardiac dysfunction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [273] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § C. Impaired Insulin Signaling

    One proposed mechanism for such an effect is increased secretion of angiotensinogen from adipocytes, especially those in visceral fat.

    “One proposed mechanism for such an effect is increased secretion of angiotensinogen from adipocytes, especially those in visceral fat (359).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [359] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § C. Impaired Insulin Signaling

    Angiotensin is thought to cause sympathoexcitation, so there may be additive effects of renin-angiotensin and sympathetic activation with respect to blood pressure elevation and cardiac remodeling in obesity.

    “Angiotensin is thought to cause sympathoexcitation, so there may be additive effects of renin-angiotensin and sympathetic activation with respect to blood pressure elevation and cardiac remodeling in obesity (67).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § VI. ROLE OF ADIPOKINES IN REGULATION OF CARDIAC REMODELING

    Adipose tissue is now known to produce and secrete an ever increasing range of factors, collectively termed "adipokines".

    “Adipose tissue, once considered simply a lipid storage depot, is now known to produce and secrete an ever increasing range of factors, collectively termed “adipokines” (175).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Effects of Leptin on the Heart

    Lack of leptin or leptin resistance leads to accumulation of lipids in non-adipose peripheral tissues due to loss of leptin's antisteatotic effects and results in a variety of lipotoxic effects.

    “Lack of leptin or leptin resistance leads to accumulation of lipids in non-adipose peripheral tissues due to loss of leptin’s antisteatotic effects and results in a variety of lipotoxic effects (356).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [356] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Effects of Leptin on the Heart

    Depressed cardiac response to β-adrenergic agonists is observed in ob/ob mice and can be corrected by leptin replacement therapy.

    “Another characteristic marker of heart failure, depressed cardiac response to β-adrenergic agonists, is also observed in ob/ob mice and can be corrected by leptin replacement therapy (238).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [238] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § C. Effects of Leptin on the Heart

    Leptin mediates a myriad of effects that can impinge on development or progression of heart failure, and it is likely that too much or too little is detrimental.

    “In summary, it would appear that leptin mediates a myriad of effects that can impinge on development or progression of heart failure, and it is likely that too much or too little is detrimental.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § C. Effects of Leptin on the Heart

    Initial studies suggested that while the effects of leptin on satiety and energy metabolism were resistant, the sympathoexcitatory effects were maintained.

    “Initial studies purporting this concept suggested that while the effects of leptin on satiety and energy metabolism were resistant, the sympathoexcitatory effects were maintained (60, 61, 222, 223, 290, 291).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [60] source

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    • cites [61] source

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    • cites [222] source

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    • cites [223] source

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    • cites [290] source

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    • cites [291] source

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  • May combine two claims.

    Premisecitation
    § VI. ROLE OF ADIPOKINES IN REGULATION OF CARDIAC REMODELING

    Both full-length and globular adiponectin attenuated endothelin (ET)-1-induced hypertrophy in cultured cardiomyocytes, suggesting a potential role in the pathogenesis of ET-1-related cardiomyocyte hypertrophy after MI.

    “Thus, whereas adiponectin may mediate a direct in vitro hypertrophic effect on primary cardiomyocytes (320), another study showed that both full-length and globular adiponectin attenuated endothelin (ET)-1-induced hypertrophy in cultured cardiomyocytes, suggesting a potential role in the pathogenesis of ET-1-related cardiomyocyte hypertrophy after MI (108).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [108] source

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  • May combine two claims.

    Premisecitation
    § VI. ROLE OF ADIPOKINES IN REGULATION OF CARDIAC REMODELING

    Myocardial necrosis in obese mice with viral myocarditis was attenuated upon endogenous cardiac induction of adiponectin expression, suggesting this may represent a compensatory protective response.

    “Furthermore, myocardial necrosis in obese mice with viral myocarditis was attenuated upon endogenous cardiac induction of adiponectin expression, suggesting this may represent a compensatory protective response (167, 338, 340).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [167] source

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    • cites [338] source

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    • cites [340] source

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  • May combine two claims.

    Premisecitation
    § C. Effects of Leptin on the Heart

    Leptin may impact myocardial function via direct peripheral effects or via secondary central nervous system-mediated responses, and there is an extensive literature documenting that leptin can influence many parameters associated with obesity and heart failure.

    “Importantly, leptin may impact on myocardial function via direct peripheral effects or via secondary central nervous system-mediated responses, and there is an extensive literature documenting that leptin can influence many parameters associated with obesity and heart failure (216, 289).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [216] Luo JD, Zhang GS, Chen MS.Leptin and cardiovascular diseases.Timely Top Med Cardiovasc Dis9: E34, 2005.

      Not checked in the free run.

    • cites [289] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Effects of Leptin on the Heart

    The ob/ob mouse model is rather unique (plasma leptin levels are increased in almost all other obese rodent models and in humans) and may not precisely reflect the alterations observed in human obesity.

    “In general, the ob/ob mouse model is rather unique (plasma leptin levels are increased in almost all other obese rodent models and in humans, Ref. 297) and may not precisely reflect the alterations observed in human obesity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [297] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § VI. ROLE OF ADIPOKINES IN REGULATION OF CARDIAC REMODELING

    Administration of adiponectin diminished the infarct size, apoptosis, and TNF-α production induced by ischemia-reperfusion in both wild-type and adiponectin KO mice.

    “Administration of adiponectin diminished the infarct size, apoptosis, and TNF-α production induced by ischemia-reperfusion in both wild-type and adiponectin KO mice (321).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [321] source

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  • May combine two claims.

    Premisecitation
    § C. Effects of Leptin on the Heart

    Leptin-deficient ob/ob mice exhibit a higher degree of cardiomyocyte apoptosis that can be restored to normal levels by leptin administration.

    “For example, leptin-deficient ob/ob mice exhibit a higher degree of cardiomyocyte apoptosis that can be restored to normal levels by leptin administration (24).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § VI. ROLE OF ADIPOKINES IN REGULATION OF CARDIAC REMODELING

    Antidiabetic, anti-inflammatory, and antihypertensive effects have all been established to occur in response to adiponectin.

    “Antidiabetic (162), anti-inflammatory (348), and antihypertensive (259) effects have all been established to occur in response to adiponectin.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [162] source

      Not checked in the free run.

    • cites [348] source

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    • cites [259] source

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  • May combine two claims.

    Premisecitation
    § VI. ROLE OF ADIPOKINES IN REGULATION OF CARDIAC REMODELING

    Pressure overload-induced concentric hypertrophy was enhanced in adiponectin-deficient mice and led to increased mortality that was corrected by adiponectin replacement.

    “Similarly, pressure overload-induced concentric hypertrophy was enhanced in adiponectin-deficient mice and led to increased mortality that was corrected by adiponectin replacement (320).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [320] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § VI. ROLE OF ADIPOKINES IN REGULATION OF CARDIAC REMODELING

    In a small number of autopsy specimens, adiponectin was not found in individuals without cardiac lesions, but it was detected in patients who suffered MI or dilated cardiomyopathy.

    “Adiponectin was not found in individuals without cardiac lesions, but it was detected in patients who suffered MI or dilated cardiomyopathy (339).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [339] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § VI. ROLE OF ADIPOKINES IN REGULATION OF CARDIAC REMODELING

    Adiponectin caused a small but significant increase in glucose and fatty acid uptake and induced AMPK phosphorylation in cultured neonatal rat cardiomyocytes and mouse HL-1 cells.

    “Adiponectin caused a small but significant increase in glucose and fatty acid uptake and induced AMPK phosphorylation in cultured neonatal rat cardiomyocytes and mouse HL-1 cells (281).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [281] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Effects of Leptin on the Heart

    Another caveat of the ob/ob model for the study of hypertrophy is the presence of low arterial pressure, while the opposite is found in most forms of obesity.

    “Another caveat of this model for the study of hypertrophy is the presence of low arterial pressure, while the opposite is found in most forms of obesity (224).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [224] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § C. Effects of Leptin on the Heart

    One report concluded that leptin mediates antihypertrophic effects since infusion of leptin to ob/ob mice, which exhibit LVH, decreased LV wall thickness.

    “One report concluded that leptin mediates antihypertrophic effects since infusion of leptin to ob/ob mice, which exhibit LVH, decreased LV wall thickness (23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisereasoning
    § VIII. PERSPECTIVES

    Multiple studies showing improved survival in obese patients with established cardiovascular disease has led to the concept of "the obesity paradox."

    “Multiple studies showing improved survival in obese patients with established cardiovascular disease has led to the concept of “the obesity paradox.””
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § VII. CLINICAL ISSUES

    Many studies have shown that weight loss improves blood pressure, diabetes, sleep apnea, hyperlipidemia, and sympathetic/parasympathetic tone.

    “Many studies have shown that weight loss improves blood pressure, diabetes, sleep apnea, hyperlipidemia, and sympathetic/parasympathetic tone (196, 284, 324, 365).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [196] source

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    • cites [284] source

      Not checked in the free run.

    • cites [324] source

      Not checked in the free run.

    • cites [365] source

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  • May combine two claims.

    Premisecitation
    § VII. CLINICAL ISSUES

    Pharmacotherapy with orlistat and sibutramine have both been associated with weight loss, improvements in serum lipids, and insulin sensitivity.

    “Pharmacotherapy with the two currently approved drugs for obesity treatment, orlistat (a gastrointestinal lipase inhibitor) and sibutramine (a monoamine reuptake inhibitor), have both been associated with weight loss, improvements in serum lipids, and insulin sensitivity (76, 109, 270).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [76] source

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    • cites [109] source

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    • cites [270] source

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  • May combine two claims.

    Premisecitation
    § VII. CLINICAL ISSUES

    Patients can exercise longer and they report less dyspnea and chest pain after significant weight loss.

    “Perhaps more importantly, patients can exercise longer and they report less dyspnea and chest pain after significant weight loss (168).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § VII. CLINICAL ISSUES

    Bariatric surgery in general produces much greater amounts of weight loss than life-style modification or pharmacotherapy, and these losses are usually sustained for much longer.

    “Nonetheless, bariatric surgery in general produces much greater amounts of weight loss than life-style modification or pharmacotherapy, and these losses are usually sustained for much longer (324).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [324] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § VII. CLINICAL ISSUES

    Orlistat treatment usually reduces blood pressure, while sibutramine is commonly associated with increased heart rate and blood pressure.

    “Orlistat treatment usually reduces blood pressure, while sibutramine is commonly associated with increased heart rate and blood pressure (109, 393).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [109] source

      Not checked in the free run.

    • cites [393] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § C. Effects of Leptin on the Heart

    In a high-fat induced model of obesity in mice, leptin resistance measured by STAT-3 activation was shown to be restricted to the arcuate nucleus of the hypothalamus, and this correlated with expression of the suppressor of leptin signaling SOCS-3.

    “Indeed, using a high-fat induced model of obesity in mice, leptin resistance measured by STAT-3 activation was shown to be restricted to the arcuate nucleus of the hypothalamus (60, 194), and this correlated with expression of the suppressor of leptin signaling SOCS-3 (248).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [60] source

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    • cites [194] source

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    • cites [248] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § VIII. PERSPECTIVES

    It seems likely that obesity influences cardiac remodeling both directly and via its closely associated comorbidities such as hypertension, diabetes, sleep-disordered breathing, kidney dysfunction, atherosclerosis, and endothelial dysfunction.

    “It seems likely that obesity influences cardiac remodeling both directly and via its closely associated comorbidities such as hypertension, diabetes, sleep-disordered breathing, kidney dysfunction, atherosclerosis, and endothelial dysfunction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § C. Effects of Leptin on the Heart

    Leptin resistance in obesity is restricted to the metabolic actions of leptin, and impaired leptin signaling was observed in ventricular cardiomyocytes isolated from rats subjected to 10-wk dietary sucrose feeding to generate hyperleptinemia and insulin resistance.

    “It was also recently suggested that leptin resistance in obesity is restricted to the metabolic actions of leptin (62), and impaired leptin signaling was observed in one study using ventricular cardiomyocytes isolated from rats subjected to 10-wk dietary sucrose feeding to generate hyperleptinemia and insulin resistance (139).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [62] source

      Not checked in the free run.

    • cites [139] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given
    § VIII. PERSPECTIVES

    There is a growing body of data showing that obesity may have protective as well as deleterious effects on the cardiovascular system.

    “Further complicating our ability to unravel the impact of obesity on human health is the growing body of data showing that obesity may have protective as well as deleterious effects on the cardiovascular system.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning
    § VIII. PERSPECTIVES

    The cumulative effects of obesity on the heart may not become clinically apparent for as much as 50 years or more.

    “However, the cumulative effects on the heart may not become clinically apparent for as much as 50 years or more.”
    Quote in the paperNot a substantial claim
131 of 131

  • The paper relies on this without support.

    Hospital discharge coding and death certificates are notoriously inaccurate for diagnosing heart failure.

    “Hospital discharge coding and death certificates are notoriously inaccurate.”

  • The paper relies on this without support.

    Traditional cardiovascular risk factors explain only a fraction of the actual myocardial infarctions that occur in the general population.

    “Although the investigators adjusted for the presence of cardiovascular risk factors, we know that traditional risk factors explain only a fraction of the actual myocardial infarctions that occur in the general population.”

  • The paper relies on this without support.

    Office-based blood pressure recordings in obese patients underestimate the burden of hypertension that would be picked up by 24-h recordings.

    “and office-based blood pressure recordings in obese patients may underestimate the burden of hypertension that would be picked up by 24-h recordings.”

  • The paper relies on this without support.

    Obesity in certain animal models is associated with coincident morbidities such as impaired glucose tolerance, diabetes, and hypertension.

    “In evaluating results from animal studies, it is important to bear in mind that similar to the situation in humans, obesity in certain animal models is associated with coincident morbidities such as impaired glucose tolerance, diabetes, and hypertension.”

  • The paper relies on this without support.

    Hypertension is highly prevalent in obese subjects (>60%) and is probably the most common cause of LV hypertrophy in the general population.

    “Hypertension is highly prevalent in obese subjects (>60%), and it is probably the most common cause of LV hypertrophy in the general population.”

  • The paper relies on this without support.

    The large fat depots in significant obesity produce a low-resistance vascular circuit that may further increase cardiac output.

    “The large fat depots in significant obesity produce a low-resistance vascular circuit that may further increase cardiac output.”

  • The paper relies on this without support.

    Obstructive sleep apnea is very common in obesity and is nearly universal in severe obesity.

    “Obstructive sleep apnea is very common in obesity and is nearly universal in severe obesity.”

  • The paper relies on this without support.

    Obese subjects have activation of the sympathetic nervous system.

    “Numerous studies show evidence that obese subjects have activation of the sympathetic nervous system.”

  • The paper relies on this without support.

    Catecholamines may have direct hypertrophic effects that are independent of hemodynamic factors.

    “In addition, catecholamines may have direct hypertrophic effects that are independent of hemodynamic factors.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Rat study described as involving obese mice

    Minor

    The sentence identifies the animals as fa/fa rats, then calls them obese mice. The cited study also identifies them as rats.

  • Leptin-signaling claim conflicts with cited study title

    Minor

    The text says the cited cardiomyocyte study observed impaired leptin signaling, whereas the cited study's title says it did not find cardiac leptin resistance.

2 of 2

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Authors
Abel, E. D., Litwin, S. E., & Sweeney, G.
Affiliations
York University (CA)
ORCID
Venue
Physiological Reviews
Publisher
American Physiological Society
Published
2008-04
Volume
88
Issue
2
Pages
389-419
ISSN
  • 0031-9333 (ISSN-L)
  • 1522-1210
DOI
10.1152/physrev.00017.2007
PMC
PMC2915933
OpenAlex
W2125861412
Semantic Scholar
5c724d949ac2a738a3723c4b568ce737a4d3bcf4
Cited by
736
References
404
Citations by year
2026: 20 · 2025: 31 · 2024: 34 · 2023: 24 · 2022: 44 · 2021: 58 · 2020: 52 · 2019: 39 · 2018: 41 · 2017: 54 · 2016: 54 · 2015: 46 · 2014: 45 · 2013: 48 · 2012: 48
FWCI
4.89
Type
journal article
Language
en
Open access
Locations
  • Physiological Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01 HL70070, R01HL073167, U01HL087947, U01-HL70525, R01-HL-73167, R01HL070070, U01HL070525)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK092065)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
obesity, cardiac remodeling, obesity paradox, heart failure, leptin, adiponectin, adipokines, cardioprotection, cardiovascular disease, myocardial structure and function, adipose tissue
MeSH terms
Animals, Disease Models, Animal, Heart, Humans, Myocardium, Obesity, Ventricular Remodeling, Adipokines

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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