Cardiac Systolic and Diastolic Dysfunction After a Cholesterol-Rich Diet

Huang, Yu‐Yuan; Walker, Katrina E.; Hanley, Frank L.; Narula, J.; Houser, Steven R.; Tulenko, T. N.

doi:10.1161/01.cir.0000109213.10461.f6

Cited by 104 publications

(109 citation statements)

References 29 publications

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“…The recapitulation of the fetal gene program (i.e., an MHC isoform switch from predominantly ␣ to ␤, decreased SERCA2a, and increased ANP) classically occurs to varying extents in response to a number of mechanical insults, including thoracic aortic constriction (15,34), pacing-induced heart failure (52), and aortocaval shunting (37). However, there is a growing body of evidence that certain metabolic disturbances, including hypothyroidism (24), dexamethasone treatment (21), gonadectomy (57), and a high-cholesterol diet (32), produce these changes as well. In light of our findings, and those of others (14,39), it would appear that insulin-resistant diabetes is no different.…”

Section: Discussionmentioning

confidence: 99%

Magnetic resonance imaging of progressive cardiomyopathic changes in the db/db mouse

Yue

Arai²,

Terashima³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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The db/db mouse is a well-established model of diabetes. Previous reports have documented contractile dysfunction (i.e., cardiomyopathy) in these animals, although the extant literature provides limited insights into cardiac structure and function as they change over time. To better elucidate the natural history of cardiomyopathy in db/db mice, we performed cardiac magnetic resonance (CMR) scans on these animals. CMR imaging was conducted with a 4.7-T magnet on female db/db mice and control db/ϩ littermates at 5, 9, 13, 17, and 22 wk of age. Gated gradient echo sequences were used to obtain cineographic short-axis slices from apex to base. From these images left ventricular (LV) mass (LVM), wall thickness, end-diastolic volume (LVEDV), and ejection fraction (LVEF) were determined. 18 F]FDG metabolic imaging showed a 40% decrease in glucose uptake in db/db mice. Furthermore, contractile dysfunction was observed in 15-wk db/db mice undergoing pressure-volume loops. Finally, real-time quantitative PCR revealed an age-dependent recapitulation of the fetal gene program, consistent with a myopathic process. In summary, as assessed by CMR, db/db mice develop characteristic structural and functional changes consistent with cardiomyopathy. diabetes mellitus; insulin resistance; heart failure; metabolism CONGESTIVE HEART FAILURE (CHF) is a significant yet often underappreciated complication of diabetes mellitus (25). While atherosclerotic coronary artery disease is highly prevalent and likely responsible for CHF in many diabetic patients, findings from several large-scale heart failure clinical trials reveal a 16 -20% prevalence of diabetes in patients with nonischemic cardiomyopathy (9). Moreover, an analysis of hospital discharge data showed a 27% prevalence of diabetes in patients discharged with idiopathic cardiomyopathy, compared with 18% for control subjects (13). Collectively these data suggest an alternative mechanism for CHF in diabetics-one independent of the effects of epicardial coronary disease. However, studies investigating this unique form of "diabetic cardiomyopathy" (51) have failed to establish a unifying mechanistic basis for this phenomenon.The C57BL/KLS-lepr db /lepr db (db/db) mouse, which has a mutation in the leptin receptor, is a well-established animal model of Type 2 diabetes mellitus (19). Leptin resistance results in hyperphagia and weight gain from birth. Homozygous db/db mice become noticeably obese by 3-4 wk of age and develop hyperglycemia at 4 -8 wk. Serum insulin levels increase as early as 10 -14 days, peak at 6 -8 wk, then decrease precipitously afterward (although db/db mice continue to be hyperinsulinemic throughout life). This drop, which is believed to be secondary to pancreatic islet cell dysfunction, further exacerbates the hyperglycemia.In addition to these characteristic phenotypic changes, db/db mice also develop cardiomyopathy. Metabolic experiments using cultured db/db cardiomyocytes have shown impaired glucose oxidation as early as 6 wk of age (1). Echocardiographic studie...

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Section: Discussionmentioning

confidence: 99%

Magnetic resonance imaging of progressive cardiomyopathic changes in the db/db mouse

Yue

Arai²,

Terashima³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…Although the gap junction remodeling proceeded the statistically significant reduction in CVI, Sm and impairment of Tei index, the presentation of temporal profile may not be enough to establish a cause-effect relation between them, because the myosin isoform redistribution and downregulation of SERCA-2 have been observed in the failing myocardium. 36 Further experiments will be required to disclose the critical role of contractile synchronism of normal myocytes in generating CVI.…”

Section: Discussionmentioning

confidence: 99%

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

Lin

Yeh

et al. 2005

Laboratory Investigation

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The effects of hypercholesterolemia on the myocardium per se include electrophysiological and mechanical alterations. Since gap junctions are essential in electromechanical coupling throughout the heart, we examined the correlation between the temporal expression of cardiac connexin 43 (Cx43), contractile function, and conduction velocity in cholesterol-fed rabbits. After a 12-week feeding period, serum cholesterol levels gradually increased (Po0.001). In contrast, expression of cardiomyocyte Cx43 protein progressively decreased (60% reduction at 12 weeks, Po0.001). Such a reduction was also demonstrated by immunoconfocal microscopy, which further showed redistribution of Cx43 gap junctions at the lateral cell membrane. The downregulation of Cx43 protein was associated with increased levels of Cx43 mRNA (3.5 -fold at 12 weeks, Po0.001) and phosphorylated c-Jun N-terminal kinase (three-fold at 12 weeks, P ¼ 0.001). Functionally, although fractional shortening of the left ventricle remained unchanged throughout the feeding protocol, the cholesterol-fed rabbits had a reduced cardiac cycle-dependent variation of integrated backscatters, a decreased mitral ring systolic velocity, and an increased modified Tei index (all Po0.001), all of which indicated impaired intrinsic myocardial contractility and attenuated ventricular systolic performance. In Langendorff-perfused hearts of cholesterol-fed rabbits, decreased conduction velocity was observed (Po0.005). Withdrawal of the cholesterol-enriched diet for 18 weeks restored the contractile parameters and Cx43 protein expression. These findings suggest that Cx43 is highly involved in the molecular mechanism of hypercholesterolemia-induced cardiac contractile dysfunction and dysrhythmias.

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“…However, these rabbit studies should be interpreted with caution. Indeed, plasma cholesterol levels in these studies were approximately 500 mg/dl [73] and 800 mg/dl [74], which is rarely observed in humans.…”

Section: Non-hdl Lipoproteinsmentioning

confidence: 67%

“…Data on the effect of cholesterol on in vivo systolic and diastolic function are paralleled by observations in isolated cardiomyocytes showing a decrease in the maximum rate of cardiomyocyte shortening and the maximum rate of cardiomyocyte 395 relaxation [74,75]. Based on these observations, the term 'cholesterol cardiomyopathy' has been introduced [74].…”

Section: Non-hdl Lipoproteinsmentioning

confidence: 96%

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Role of lipids and lipoproteins in myocardial biology and in the development of heart failure

Muthuramu¹,

Singh²,

Amin³

et al. 2015

Clinical Lipidology

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As the population ages, heart failure will continue to be a growing public health 30 problem. Metabolic homeostasis in the heart requires a fine-tuning of metabolism of different substrates. Notwithstanding a retro control of fatty acid and glucose utilization, the heart functions best when it oxidizes both substrates simultaneously.Mismatch between the uptake and oxidation of long-chain fatty acids in the myocardium induces lipotoxicity characterized by the accumulation of triglycerides, 35 diacylglycerols, ceramides, and other lipids. Lipotoxicity may result in cardiomyocyte apoptosis, interstitial fibrosis, and cardiac dysfunction, and may promote insulin resistance. In this review, we will highlight the impact of lipids and lipoproteins on myocardial biology and on the development of heart failure independent of their effects on coronary heart disease. 40 45 KEY WORDSHeart failure, cardiac metabolism, fatty acids, lipotoxicity, hypercholesterolemia, high-density lipoproteins 50 3

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Cardiac Systolic and Diastolic Dysfunction After a Cholesterol-Rich Diet

Abstract: These data demonstrate that dietary hypercholesterolemia induces a "cholesterol cardiomyopathy" characterized by systolic and diastolic dysfunction. These alterations were independent of vascular disease and demonstrate a dietary link to cardiac dysfunction.

Cited by 104 publications

References 29 publications

Magnetic resonance imaging of progressive cardiomyopathic changes in the db/db mouse

Magnetic resonance imaging of progressive cardiomyopathic changes in the db/db mouse

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

Role of lipids and lipoproteins in myocardial biology and in the development of heart failure

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