Diabetes Mellitus Worsens Diastolic Left Ventricular Dysfunction in Aortic Stenosis Through Altered Myocardial Structure and Cardiomyocyte Stiffness

Falcão-Pires, Inês; Hamdani, Nazha; Borbély, Attila; Gavina, Cristina; Schalkwijk, Casper G.; Velden, Jolanda van der; Heerebeek, Loek van; Stienen, G. J. M.; Niessen, Hans W.M.; Leite‐Moreira, Adelino F.; Paulus, Walter J.

doi:10.1161/circulationaha.111.025270

Cited by 203 publications

(172 citation statements)

References 47 publications

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“…An increased proportion of the compliant N2BA variants was observed in end-stage failing human hearts, including those from ischemic cardiomyopathy, 105 nonischemic DCM, 109,110 and other patients with HFrEF, 111 compared with nonfailing donor hearts (45%-50% versus ≈30%). In patients with aortic stenosis, the N2BA:N2B expression ratio was somewhat higher than in healthy control hearts in one study, 111 but unaltered 112 or reduced 113 in other studies. In the hearts of mice exposed to transverse aortic constriction, the N2BA:N2B ratio was significantly increased in comparison with healthy mouse hearts.…”

Section: Adjustment Of Titin Stiffness By Isoform Switching In Nonfaimentioning

confidence: 74%

“…117,125 A few studies have reported an increased ratio of phospho-N2BA:phospho-N2B in human HF, including HFpEF, aortic stenosis, and HFrEF. 111,112 However, as the N2BA:N2B isoform-expression ratio was also increased in these patient hearts, the proportion of phospho-titin to all-titin (per isoform) may have been similar in the nonfailing and failing hearts. Unaltered total-titin phosphorylation was recently found in end-stage failing DCM patients, compared with nonfailing donor hearts.…”

Section: Altered Titin Phosphorylation In Hf and Implications For Diamentioning

confidence: 88%

“…In contrast, the deficit for PKAand PKG-dependent phosphorylation at the N2-Bus element may contribute substantially to the increased diastolic stiffness observed in failing hearts ( Figure 7F). Support for this view comes from the observation that PKA or PKG (administered ex vivo) corrected the pathologically high passive stiffness of isolated cardiomyocytes in human HFpEF, HFrEF, and aortic stenosis with or without diabetes mellitus, 6,111,112,149 as well as in animal models of HFpEF 117,125 ( Figure 7F). Patients with HFpEF had higher cardiomyocyte passive tension than patients with HFrEF, and recombinant PKA or PKG tended to reduce this parameter more strongly in HFpEF than in HFrEF or aortic stenosis ( Figure 7F), 111,149 which could be because of a larger phosphorylation deficit at the N2-Bus in HFpEF than in HFrEF/aortic stenosis.…”

Section: Altered Titin Phosphorylation In Hf and Implications For Diamentioning

confidence: 92%

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Linke

Hamdani

2014

Circulation Research

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With every heartbeat, our cardiomyocytes are exposed to variable degrees of stress and strain of both internal and external origin. The unique mechanical properties of these myocytes are determined by the sarcomeric cytoskeleton. The actin (thin) and myosin (thick) filaments of the sarcomere are mainly relevant for active force generation, whereas the titin filaments determine sarcomeric viscoelasticity. The giant protein titin, which is the focus of this review, has various roles beyond viscoelastic force generation 1-3 : (1) it keeps the thick filaments centered in the sarcomere, allowing optimum active force development; (2) it is important for the assembly of the sarcomeres; (3) it participates in mechano-chemical signaling events via some of its binding partners; and (4) it may be crucial for the length-dependent activation of the contractile apparatus, which underlies the Frank-Starling law. During the past decade, we have learned that titin elasticity is highly variable in the developing and the adult healthy heart and that it can be pathologically altered in heart disease. These alterations greatly affect the extensibility and the diastolic passive stiffness of myocardium and presumably also the mechanosensitivity. Moreover, TTN, which encodes the titin protein, has been recognized as a major human disease gene. In this context, the properties and functions of cardiac titin have become of interest in the continuing search for the molecular origins of human heart disease and the identification of novel potential targets for therapeutic intervention. In our review, we begin with a short clinical perspective establishing the link between diastolic stiffness and titin and briefly compare the importance of titin versus collagen for myocardial passive stiffness. We then cover some details of titin protein structure and elasticity, before summarizing how titin-binding partners affect titin properties and broaden the range of titin functions, with a special focus on the standing of titin in pathways of protein quality control. We continue with a current overview of titin mutations in human skeletal muscle and heart disease. The remainder of the review deals with the contribution of titin to diastolic stiffness and how it is modulated in normal and failing hearts by mechanisms such as titin-isoform switching, titin phosphorylation (including heart failure [HF]-related alterations of it), and oxidative modifications. Clinical Context: Diastolic Function and Diastolic AbnormalitiesDiastolic function has moved into the focus of HF research, because an increasing number of patients with HF (≥50%) present with diastolic rather than systolic dysfunction. 4 Common abnormalities of diastolic function include impaired left ventricular (LV) relaxation, decreased LV distensibility, increased LV end-diastolic stiffness, and pericardial and right ventricular constraint. These abnormalities have been suggested to be contributing factors in diastolic HF or HF with a preserved ejection fraction (HFpEF).5 HFpEF is accompanied by ...

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Section: Adjustment Of Titin Stiffness By Isoform Switching In Nonfaimentioning

confidence: 74%

Section: Altered Titin Phosphorylation In Hf and Implications For Diamentioning

confidence: 88%

Section: Altered Titin Phosphorylation In Hf and Implications For Diamentioning

confidence: 92%

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Gigantic Business

Linke

Hamdani

2014

Circulation Research

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292

232

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“…Aortic stenosis patients with diabetes mellitus, a frequent pathology in older patients, increases LV afterload and exhibits reduced LV distensibility compared to aortic stenosis patients without diabetes mellitus, indicating that disease complicated with comorbidities may result in more severe diastolic dysfunction (Paulus 2010;Paulus and Tschöpe 2013). Aortic stenosis with diabetes mellitus is associated with incre ased c ollagen volume fraction, increa sed intramyocardial vascular advanced glycation end product deposition, and high cardiomyocyte stiffness, in addition to titin hypophosphorylation (Falcão-Pires et al 2011;Borbély et al 2005;van Heerebeek et al 2006van Heerebeek et al , 2008Hamdani and Paulus 2011;Hamdani et al 2013aHamdani et al , b, 2014.…”

Section: •-mentioning

confidence: 99%

A change of heart: oxidative stress in governing muscle function?

Breitkreuz

Hamdani

2015

Biophys Rev

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Redox/cysteine modification of proteins that regulate calcium cycling can affect contraction in striated muscles. Understanding the nature of these modifications would present the possibility of enhancing cardiac function through reversible cysteine modification of proteins, with potential therapeutic value in heart failure with diastolic dysfunction. Both heart failure and muscular dystrophy are characterized by abnormal redox balance and nitrosative stress. Recent evidence supports the synergistic role of oxidative stress and inflammation in the progression of heart failure with preserved ejection fraction, in concert with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signalling via modification of the giant protein titin. Although antioxidant therapeutics in heart failure with diastolic dysfunction have no marked beneficial effects on the outcome of patients, it, however, remains critical to the understanding of the complex interactions of oxidative/nitrosative stress with pro-inflammatory mechanisms, metabolic dysfunction, and the redox modification of proteins characteristic of heart failure. These may highlight novel approaches to therapeutic strategies for heart failure with diastolic dysfunction. In this review, we provide an overview of oxidative stress and its effects on pathophysiological pathways. We describe the molecular mechanisms driving oxidative modification of proteins and subsequent effects on contractile function, and, finally, we discuss potential therapeutic opportunities for heart failure with diastolic dysfunction.

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“…Myocardial fibrosis in DCM usually leads to ventricular diastole and contractile function disorders, and ultimately to congestive heart failure (14). Myocardial fibrosis is tightly linked to the high incidence and mortality associated with DCM.…”

Section: Introductionmentioning

confidence: 99%

High glucose induces Rho/ROCK-dependent visfatin and typeï¿½I procollagen expressionï¿½inï¿½rat primaryï¿½cardiac fibroblasts

et al. 2014

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Abstract. Myocardial fibrosis and excessive proliferation of cardiac fibroblasts (CFs) contribute to diabetic cardiomyopathy (DCM). However, the underlying mechanism is still not completely clear. The aim of this study was to investigate the relationship between high-glucose treatment and the expression of visfatin and type I procollagen in rat CFs, and examine the regulatory effects of high-glucose treatment on the Rho/ROCK signaling pathway. CFs from newborn Sprague Dawley rats were treated with high concentrations of glucose (10, 30 and 50 mmol/l D-glucose), a baseline concentration of glucose (5.5 mmol/l) as a control, and mannitol (5.5 mmol/l D-glucose + 44.5 mmol/l mannitol) as an osmotic control. CFs were also treated with 30 mmol/l D-glucose for 6, 12, 24 and 48 h. The proliferation of CFs was determined by the MTT assay. The mRNA and protein expression of visfatin and type I procollagen were quantified by RT-qPCR and western blot analysis, respectively. Cardiac fibroblast proliferation reached a peak at 30 mmol/l D-glucose, and visfatin and type I procollagen expression were significantly increased upon treatment with high concentrations of glucose (10 and 30 mmol/l) compared to baseline glucose treatment. Treatment with 30 mmol/l D-glucose time-dependently promoted cardiac fibroblast proliferation. The mRNA and protein expression of visfatin and type I procollagen were significantly increased compared to the control at 24 h after 30 mmol/l D-glucose treatment. Y27632, a Rho-associated protein kinase (ROCK) inhibitor, significantly decreased the mRNA and protein levels of visfatin and type I procollagen, induced by 30 mmol/l D-glucose (all P<0.05). In conclusion, a high level of glucose promotes cardiac fibroblast proliferation, and induces visfatin and type I procollagen expression in CFs, at least partially via the Rho/ROCK signaling pathway. These results may be helpful in developing an appropriate therapeutic strategy for DCM.

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Diabetes Mellitus Worsens Diastolic Left Ventricular Dysfunction in Aortic Stenosis Through Altered Myocardial Structure and Cardiomyocyte Stiffness

Cited by 203 publications

References 47 publications

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A change of heart: oxidative stress in governing muscle function?

High glucose induces Rho/ROCK-dependent visfatin and typeï¿½I procollagen expressionï¿½inï¿½rat primaryï¿½cardiac fibroblasts

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