Abstract:
:Sixteen years ago, mutations in cardiac troponin (Tn)T and α-tropomyosin were linked to familial hypertrophic cardiomyopathy, thus transforming the disorder from a disease of the β-myosin heavy chain to a disease of the cardiac sarcomere. From the outset, studies suggested that mutations in the regulatory thin filament caused a complex, heterogeneous pattern of ventricular remodeling with wide variations in clinical expression. To date, the clinical heterogeneity is well matched by an extensive array of nearly 100 independent mutations in all components of the cardiac thin filament. Significant advances in our understanding of the biophysics of myofilament activation, coupled to the emerging evidence that thin filament linked cardiomyopathies are progressive, suggests that a renewed focus on the most proximal events in both the molecular and clinical pathogenesis of the disease will be necessary to achieve the central goal of using genotype information to manage affected patients. In this review, we examine the existing biophysical and clinical evidence in support of a more proximal definition of thin filament cardiomyopathies. In addition, new high-resolution, integrated approaches are presented to help define the way forward as the field works toward developing a more robust link between genotype and phenotype in this complex disorder.
journal_name
Circ Resjournal_title
Circulation researchauthors
Tardiff JCdoi
10.1161/CIRCRESAHA.110.224170subject
Has Abstractpub_date
2011-03-18 00:00:00pages
765-82issue
6eissn
0009-7330issn
1524-4571pii
108/6/765journal_volume
108pub_type
杂志文章,评审abstract::The endothelial cell membrane glycoprotein thrombomodulin (TM) plays a critical role in the regulation of coagulation. TM is an essential cofactor in protein C activation by thrombin, and a direct inhibitor of thrombin-induced platelet activation and fibrinogen clotting. Protease nexin-1 (PN-1) is a serpin synthesized...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000265066.92923.ee
更新日期:2007-04-27 00:00:00
abstract::A surgical technique was developed to place sutures around the pulmonary arteries of young rats (about 1 month old and 100 g body weight). As the operated rats grew, the pulmonary arteries were gradually constricted, leading after 4-6 weeks to the development of severe right ventricular hypertrophy with free wall weig...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.49.6.1300
更新日期:1981-12-01 00:00:00
abstract::G-protein receptor kinase 2 (GRK2) is 1 of 7 mammalian GRKs that phosphorylate ligand-bound 7-transmembrane receptors, causing receptor uncoupling from G proteins and potentially activating non-G-protein signaling pathways. GRK2 is unique among members of the GRK family in that its genetic ablation causes embryonic le...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000247932.71270.2c
更新日期:2006-10-27 00:00:00
abstract::In nonischemic heart failure (HF), ventricular tachycardia initiates by a nonreentrant mechanism, but there is altered conduction (that could lead to re-entry) that could arise from changes in gap junctional proteins, especially connexin43 (Cx43). We studied Cx43 expression and phosphorylation state in the left ventri...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000152325.07495.5a
更新日期:2005-01-07 00:00:00
abstract:RATIONALE:Thioredoxin (Trx)1 inhibits pathological cardiac hypertrophy. MicroRNAs (miRNAs) are small noncoding RNAs that downregulate posttranscriptional expression of target molecules. OBJECTIVES:We investigated the role of miRNAs in mediating the antihypertrophic effect of Trx1 on angiotensin II (Ang II)-induced car...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.110.228437
更新日期:2011-02-04 00:00:00
abstract:RATIONALE:The dramatic upregulation of αvβ3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for antiangiogenic therapy to treat cancer. This discovery led to the development of small-molecule inhibitors directed against α...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.114.301591
更新日期:2014-01-03 00:00:00
abstract::If the control of infectious diseases was the public health success story of the first half of the 20th century, then the decline in mortality from coronary heart disease and stroke has been the success story of the century's past 4 decades. The early phase of this decline in coronary heart disease and stroke was unex...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.116.309115
更新日期:2017-01-20 00:00:00
abstract::Heterozygous familial hypercholesterolemia (FH) is a highly atherogenic genetic disorder leading to premature coronary heart disease (CHD), usually before 60 years of age. We studied an extended multigenerational kindred with FH linked to chromosome 1p32 in which atherosclerotic complications were either delayed or pr...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000064174.69165.66
更新日期:2003-03-21 00:00:00
abstract:RATIONALE:We have recently shown that the bone morphogenetic protein (BMP) antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. Our initial studies discovered that Grem2 is strongly induced in the adult heart after experimental myocardial infarction (MI). However, th...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.116.308700
更新日期:2016-07-22 00:00:00
abstract::It has been shown previously that serotonin stimulates the production of prostacyclin by bovine aortic smooth muscle cells in culture, via 5-HT2 receptors (Coughlin SR, Moskowitz MA, Antoniades HN, Levine L. Proc Natl Acad Sci USA 1981;78:7134-7138). These cells express a synthetic phenotype, whereas the majority of t...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.64.4.806
更新日期:1989-04-01 00:00:00
abstract::Ventricular repolarization was analyzed by measuring epicardial potential distributions in intact dogs with single or multiple ectopic foci and a minimum at the terminal site(s) of excitation. During the latter half of the T wave the distributions became more complex, and two maxima evolved from the initial one at eac...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.39.4.475
更新日期:1976-10-01 00:00:00
abstract::By making use of immunoblotting and immunocytochemical analysis, we explored whether stimulation of adenosine A1 receptors would promote the activation of delta-protein kinase C (delta-PKC) immunolabeled with a polyclonal antibody. Immunoblot analysis of Triton X-100-soluble cell membrane and cytosolic fractions revea...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.78.1.161
更新日期:1996-01-01 00:00:00
abstract::The influence of endothelin 1 on intracellular Ca2+ transients and isometric contractions was investigated in ferret papillary muscles loaded with the Ca(2+)-regulated bioluminescent indicator aequorin. In concentrations of 3 x 10(-9) to 1 x 10(-7) M, endothelin produced dose-dependent increases in the amplitudes of b...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.69.3.582
更新日期:1991-09-01 00:00:00
abstract::A narrow zone of block in isolated false tendon preparations was created by perfusion of the central compartment (gap) of a three-compartment tissue bath with either an isotonic sucrose solution or a solution designed to mimic the extracellular milieu in ischemic tissue. Driven responses on the proximal side of the ga...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.49.5.1129
更新日期:1981-11-01 00:00:00
abstract::In studies that attempt to measure intracellular calcium [( Ca2+]i) in the intact heart with the calcium indicator indo 1-AM, a fundamental assumption is that the signals report changes in myocyte [Ca2+]i. We studied isolated perfused rabbit hearts loaded with the calcium probe indo 1-AM and recorded surface fluoresce...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.67.2.415
更新日期:1990-08-01 00:00:00
abstract::To assess the relation between atrial natriuretic peptide and ventricular dysfunction, we simultaneously measured both atrial and plasma immunoreactive atrial natriuretic peptide concentrations in rats 4 weeks after myocardial infarction induced by left coronary artery ligation. When compared to controls (n = 39), rat...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.59.3.256
更新日期:1986-09-01 00:00:00
abstract::Coronary pressure-flow relations during autoregulated and vasodilated flow states were compared between eight dogs with renovascular hypertension and left ventricular hypertrophy and 12 normal dogs. Each relation was constructed from serial steady-state measurements of end-diastolic coronary pressure and flow during p...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.65.1.224
更新日期:1989-07-01 00:00:00
abstract:RATIONALE:Myocardial ischemia-reperfusion (I/R) results in the generation of oxygen-derived free radicals and the accumulation of lipid peroxidation-derived unsaturated aldehydes. However, the contribution of aldehydes to myocardial I/R injury has not been assessed. OBJECTIVE:We tested the hypothesis that removal of a...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.114.305518
更新日期:2015-08-14 00:00:00
abstract::Acute increases in arterial pulsatile load imposed on the left ventricle can increase coronary flow without commensurate changes in myocardial oxygen consumption. One explanation is that augmenting pulsatile perfusion at the same mean pressure itself stimulates flow by releasing endothelium-mediated vasorelaxant facto...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.79.4.849
更新日期:1996-10-01 00:00:00
abstract::Tissue repair after injury is generally inversely related to the extent of scarring, suggesting the possibility that regeneration could be promoted by interventions that inhibit scar formation. New work by Dulauroy et al has identified a myofibroblast progenitor with pericyte characteristics as an important mediator o...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.111.300287
更新日期:2013-01-18 00:00:00
abstract::Recent studies have suggested a proangiogenic effect of angiotensin-converting enzyme (ACE) inhibition. We hypothesized that such a proangiogenic effect of ACE inhibition may be mediated, in part, by bradykinin (BK) B(2)-receptor pathway. This study therefore examined the neovascularization induced by ACE inhibitor tr...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/hh2001.097691
更新日期:2001-10-12 00:00:00
abstract::Thrombin stimulates synthesis and secretion of endothelin-1 (ET-1), a vasoactive peptide that triggers responses in the vascular endothelium and smooth muscle. We investigated the signal transduction pathways by which thrombin stimulates preproET-1 gene expression and ET-1 peptide secretion in macrovascular cells (hum...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.76.6.987
更新日期:1995-06-01 00:00:00
abstract:RATIONALE:Lymphatic vasculature constitutes a second vascular system essential for immune surveillance and tissue fluid homeostasis. Maturation of the hierarchical vascular structure, with a highly branched network of capillaries and ducts, is crucial for its function. Environmental cues mediate the remodeling process,...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.116.308825
更新日期:2017-04-14 00:00:00
abstract::Phospholamban is a key regulatory protein that defines diastolic function. Proinflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) can depress contractility and intracellular Ca2+ currents and transients. An alteration in phospholamban expression is a possible pathway by wh...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.81.4.493
更新日期:1997-10-01 00:00:00
abstract::We investigated the combined effectiveness of intra-aortic balloon counterpulsation and hyperosmotic mannitol (25%) on regional myocardial blood flow during acute coronary insufficiency. Cardiac output and paced heart rate were held constant in chloralose-anesthetized dogs during right heart bypass. Acute coronary ins...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.38.6.506
更新日期:1976-06-01 00:00:00
abstract::The goal of this study was to test the hypothesis that the cardioprotective effects of the late phase of ischemic preconditioning (PC) can be mimicked by treatment with NO donors. In phase I (studies of myocardial stunning), conscious rabbits underwent a sequence of six 4-minute coronary occlusion/4-minute reperfusion...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.83.1.73
更新日期:1998-07-13 00:00:00
abstract:RATIONALE:Inhibition of glycogen synthase kinase-3 (GSK-3) protects the heart during ischemia/reperfusion (I/R), yet the underlying mechanisms of cardioprotection afforded by beta isoform-specific inhibition GSK-3 remain to be elucidated. OBJECTIVE:We studied the molecular mechanism mediating the effect of GSK-3β acti...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.111.249532
更新日期:2011-08-19 00:00:00
abstract::The impact of vanadate on the Na,K-ATPase system in the vascular smooth muscle cell is poorly understood. The present study describes the kinetics of the effect of vanadate on Na,K-ATPase and the Na-K pump in in vitro grown rat VSMC's. Vanadate interaction with the Na,K-ATPase system in vascular smooth muscle cells wa...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.53.2.186
更新日期:1983-08-01 00:00:00
abstract::In our morphometric study of the effects of exercise on the heart, male Wistar-Kyoto rats at 5 weeks of age were subjected daily to a moderate treadmill running program that lasted for 7 weeks. The heart responded to physical conditioning by different magnitudes of tissue growth of the right (22%) and left (7%) ventri...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.52.1.57
更新日期:1983-01-01 00:00:00
abstract::The deposition of microspheres in small tissue regions is not strictly flow dependent. In comparison with the soluble flow marker 2-iododesmethylimipramine (IDMI), deposition of 16.5-microns microspheres was mildly but systematically biased into high flow regions of rabbit hearts (Bassingthwaighte JB, Malone MA, Moffe...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.66.5.1328
更新日期:1990-05-01 00:00:00