Acute and Chronic Ventricular-Arterial Coupling in Systole and Diastole

Shapiro, Brian P.; Lam, Carolyn S.P.; Patel, Jeetendra; Mohammed, Selma F.; Krüger, Martina; Meyer, Donna; Linke, Wolfgang A.; Redfield, Margaret M.

doi:10.1161/hypertensionaha.107.090092

Cited by 68 publications

(53 citation statements)

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“…An early report demonstrated a reduced N2BA:N2B ratio in a limited number of HFpEF versus HFrEF patient hearts 6 and a follow-up study showed an increased ratio in advanced HFpEF compared with nonfailing donor hearts. 111 In contrast, a hypertensive dog model with diastolic dysfunction revealed a reduced cardiac N2BA:N2B ratio versus healthy dogs 116,117 and slightly decreased N2BA proportions appeared in the spontaneously hypertensive Figure 5. Directions, causes, and consequences of titin-isoform switching in the heart.…”

Section: Adjustment Of Titin Stiffness By Isoform Switching In Nonfaimentioning

confidence: 91%

Gigantic Business

Linke

Hamdani

2014

Circulation Research

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292

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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: 91%

Gigantic Business

Linke

Hamdani

2014

Circulation Research

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292

232

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“…Left ventricular tissue of normal adult dogs was sampled as described. 25 All procedures were conducted in full accordance with the institutional guidelines and were approved by the respective ethics committees. …”

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confidence: 99%

Protein Kinase G Modulates Human Myocardial Passive Stiffness by Phosphorylation of the Titin Springs

Krüger

Kötter

Grützner

et al. 2009

Circulation Research

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Abstract-The sarcomeric titin springs influence myocardial distensibility and passive stiffness. Titin isoform composition and protein kinase (PK)A-dependent titin phosphorylation are variables contributing to diastolic heart function. However, diastolic tone, relaxation speed, and left ventricular extensibility are also altered by PKG activation. We used back-phosphorylation assays to determine whether PKG can phosphorylate titin and affect titin-based stiffness in skinned myofibers and isolated myofibrils. PKG in the presence of 8-pCPT-cGMP (cGMP) phosphorylated the 2 main cardiac titin isoforms, N2BA and N2B, in human and canine left ventricles. In human myofibers/myofibrils dephosphorylated before mechanical analysis, passive stiffness dropped 10% to 20% on application of cGMP-PKG. Autoradiography and anti-phosphoserine blotting of recombinant human I-band titin domains established that PKG phosphorylates the N2-B and N2-A domains of titin. Using site-directed mutagenesis, serine residue S469 near the COOH terminus of the cardiac N2-B-unique sequence (N2-Bus) was identified as a PKG and PKA phosphorylation site. To address the mechanism of the PKG effect on titin stiffness, single-molecule atomic force microscopy force-extension experiments were performed on engineered N2-Bus-containing constructs. The presence of cGMP-PKG increased the bending rigidity of the N2-Bus to a degree that explained the overall PKG-mediated decrease in cardiomyofibrillar stiffness. Thus, the mechanically relevant site of PKG-induced titin phosphorylation is most likely in the N2-Bus; phosphorylation of other titin sites could affect protein-protein interactions. The results suggest that reducing titin stiffness by PKG-dependent phosphorylation of the N2-Bus can benefit diastolic function. Failing human hearts revealed a deficit for basal titin phosphorylation compared to donor hearts, which may contribute to diastolic dysfunction in heart failure. Key Words: cGMP Ⅲ nitric oxide Ⅲ diastolic function Ⅲ connectin Ⅲ passive tension M yocardial and chamber diastolic function are influenced by chamber geometry, hypertrophy, the extracellular matrix and the sarcomeric titin springs. Titins are giant proteins which exist in the heart in 2 main isoforms coexpressed in sarcomeres: a shorter, stiffer N2B-titin (3.0 MDa) and longer, more compliant N2BA isoforms (3.2 to 3.7 MDa). Differential expression of these isoforms is related to alternate gene splicing affecting the functionally elastic titin region, which is confined to the sarcomeric I-band. 1 The springy titin segment comprises regions of serially linked immunoglobulin-like (Ig) domains separated by a cardiacspecific N2-B domain and a so-called PEVK segment (rich in proline, glutamate, valine, and lysine residues). The N2BA isoforms additionally have an N2-A domain and contain more Ig domains and PEVK-rich modules compared to the N2B isoform.Differential expression of titin isoforms determines passive stiffness of the sarcomere. 2,3 A low ratio of N2BA:N2B isoforms is found in sarcome...

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“…However, we could not assess perivascular fibrosis in coronary arteries as is possible in rodents with prominent intramyocardial coronary arteries. In this elderly hypertensive model, there is elastin degradation, increased collagen, and decreased collagen solubility in the aorta, 10 and these pre-existing age-and hypertension-related changes may modify the large artery response to MC excess.…”

Section: Discussionmentioning

confidence: 98%

Mineralocorticoid Signaling in Transition to Heart Failure With Normal Ejection Fraction

et al. 2008

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Abstract-Heart failure with normal ejection fraction occurs in elderly patients with hypertensive heart disease. We hypothesized that, in such patients, mineralocorticoid receptor activation accelerates the types of ventricular and vascular remodeling and dysfunction believed important in the transition to heart failure. We tested this hypothesis by administering deoxycorticosterone acetate (DOCA) without salt loading or nephrectomy to elderly dogs with experimental hypertension. Elderly dogs were made hypertensive by renal wrapping. After 5 weeks, dogs were randomly assigned to DOCA (1 mg/kg per day IM; old hypertensive [OH]ϩDOCA; nϭ11) or not (OH; nϭ11) for 3 weeks. At week 8, conscious echocardiography and hemodynamic assessment under anesthesia were performed. DOCA resulted in further increases in conscious blood pressure (PϽ0.05) without increases in cardiac output or diastolic volume. In the conscious state, effective arterial elastance (PϽ0.05) and systemic vascular resistance (Pϭ0.06) were increased, and systemic arterial compliance (PϽ0.05) was decreased in OHϩDOCA animals. After anesthesia, instrumentation, and autonomic blockade, blood pressure was lower, whereas left ventricular (LV) systolic elastance, LV diastolic stiffness, and ex vivo myofiber diastolic stiffness were increased in OHϩDOCA animals. LV collagen was increased in OHϩDOCA animals (PϽ0.05 for all), but LV mass, LV brain natriuretic peptide, and titin isoform profiles were not. Neither aortic stiffness nor aortic structure was altered in OHϩDOCA animals. These findings suggest that age and hypertensive heart disease enhance sensitivity to exogenous mineralocorticoid administration and that mineralocorticoid receptor activation could contribute to the transition to heart failure in elderly persons by promoting increases in LV diastolic and systolic stiffness. Key Words: heart failure Ⅲ hypertension Ⅲ collagen Ⅲ diastole H eart failure (HF) with normal ejection fraction (HFnlEF) comprises nearly half of the cases of HF and poses a substantial public health problem. 1 Advanced age and systemic hypertension are the dominant risk factors for HFnlEF. The presence of neurohumoral activation in HFnlEF and its role in mediating the transition from hypertensive heart disease (HHD) to HFnlEF has not been well studied. Mineralocorticoid (MC) receptor (MR) antagonism has been repeatedly demonstrated to reduce cardiac hypertrophy and fibrosis in experimental and human hypertension. 2,3 However, in young normal animals, the hypertensive and cardiac remodeling effects of experimental MC excess are dependent on concomitant salt loading (and unilateral nephrectomy). 2,4 The mechanisms whereby salt loading exacerbates the effects of exogenous MC administration on the heart and vasculature are unclear, and other factors present in HHD, 5 vascular disease, 6 or HF 7 may also sensitize the cardiovascular system to the adverse effects of exogenous MC excess. Indeed, a recent study showed that aldosterone levels correlate potently with mortality in HF regardle...

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Acute and Chronic Ventricular-Arterial Coupling in Systole and Diastole

Cited by 68 publications

References 47 publications

Gigantic Business

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Protein Kinase G Modulates Human Myocardial Passive Stiffness by Phosphorylation of the Titin Springs

Mineralocorticoid Signaling in Transition to Heart Failure With Normal Ejection Fraction

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