Pathological Ventricular Remodeling

Xie, Min; Burchfield, Jana; Hill, Joseph A.

doi:10.1161/circulationaha.113.001879

Cited by 136 publications

(98 citation statements)

References 106 publications

(125 reference statements)

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“…Histologically, LGE in DCM corresponds to replacement fibrosis, 6,51 which seems not modifiable with treatment. 82 In patients with DCM, several pathophysiological drivers were found related to the change in T1 indices, including myocardial fibrosis, infiltration, and inflammation; the latter is an increasingly recognized underlying cause of DCM. Because of its ability to recognize subclinical diffuse myocardial involvement, as well as a measure of longitudinal changes of myocardial inflammation, T1 mapping seems promising for detecting subclinical pathophysiological changes, potentially allowing us to modify the course of disease.…”

Section: T1 Mapping In Nonischemic Dilative Cardiomyopathymentioning

confidence: 99%

T1 Mapping in Characterizing Myocardial Disease

Püntmann

Peker

Chandrashekhar

et al. 2016

Circulation Research

271

202

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Cardiovascular magnetic resonance provides insights into myocardial structure and function noninvasively, with high diagnostic accuracy and without ionizing radiation. Myocardial tissue characterization in particular gives cardiovascular magnetic resonance a prime role among all the noninvasive cardiovascular investigations. Late gadolinium enhancement imaging is an established method for visualizing replacement scar, providing diagnostic and prognostic information in a variety of cardiac conditions. Late gadolinium enhancement, however, relies on the regional segregation of tissue characteristics to generate the imaging contrast. Thus, myocardial pathology that is diffuse in nature and affecting the myocardium in a rather uniform and global distribution is not well visualized with late gadolinium enhancement. Examples include diffuse myocardial inflammation, fibrosis, hypertrophy, and infiltration. T1 mapping is a novel technique allowing to diagnose these diffuse conditions by measurement of T1 values, which directly correspond to variation in intrinsic myocardial tissue properties. In addition to providing clinically meaningful indices, T1-mapping measurements also allow for an estimation of extracellular space by calculation of extracellular volume fraction. Multiple lines of evidence suggest a central role for T1 mapping in detection of diffuse myocardial disease in early disease stages and complements late gadolinium enhancement in visualization of the regional changes in common advanced myocardial disease. As a quantifiable measure, it may allow grading of disease activity, monitoring progress, and guiding treatment, potentially as a fast contrast-free clinical application. We present an overview of clinically relevant technical aspects of acquisition and processing, and the current state of art and evidence, supporting its clinical use.

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Section: T1 Mapping In Nonischemic Dilative Cardiomyopathymentioning

confidence: 99%

T1 Mapping in Characterizing Myocardial Disease

Püntmann

Peker

Chandrashekhar

et al. 2016

Circulation Research

271

202

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“…Although angiotensin blockade has recognized direct antifibrotic effects, 4,5,22,25,35,36 ACEi only delay the progression of organ fibrosis by months and can have undesirable side effects when chronically administered. The increased antifibrotic efficacy of serelaxin seen here in the injured heart makes it a highly desirable therapeutic agent for the attenuation of organ fibrosis.…”

Section: Perspectivesmentioning

confidence: 99%

Serelaxin Is a More Efficacious Antifibrotic Than Enalapril in an Experimental Model of Heart Disease

Samuel¹,

Bodaragama²,

Chew³

et al. 2014

Hypertension

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Abstract-Relaxin is a naturally occurring peptide hormone that mediates systemic hemodynamic and renal adaptive changes during pregnancy and abrogates aberrant scar tissue formation (fibrosis) in diverse pathogeneses. However, its efficacy relative to renin-angiotensin system blockade, the most effective antifibrotic strategy currently available, is not known. We compared the individual versus combined antifibrotic effects of serelaxin (a recombinant form of human gene-2 relaxin) and the angiotensin-converting enzyme inhibitor enalapril, in preventative (started before injury) and therapeutic (treatment of established fibrosis) strategies, in a mouse model of isoprenaline-induced cardiac injury (at 17 days). Changes in systolic blood pressure, organ hypertrophy, and tissue remodeling/fibrosis were assessed. Pretreatment with serelaxin (0.5 mg/kg per day via subcutaneous administration) alone reduced cardiac fibrosis to a greater extent than enalapril (200 mg/L via drinking water; equivalent to 48 mg/kg per day) alone (P<0.05 versus enalapril alone). Additionally, the combined effects of serelaxin and enalapril reduced cardiac fibrosis by at least 2-fold compared with enalapril alone, when administered preventatively or therapeutically; by suppressing transforming growth factor-β1 expression and phosphorylation of Smad2 (an intracellular regulator of transforming growth factor-β1 activity; both P<0.05 versus enalapril alone) to a greater extent. The effects of serelaxin were independent of blood pressure, while enalapril lowered systolic blood pressure in the model studied. These findings suggest that serelaxin alone and in combination with an angiotensin-converting enzyme inhibitor more effectively ameliorates fibrosis than angiotensin-converting enzyme inhibition alone in the diseased heart, in a clinically relevant experimental scenario. (Hypertension. 2014;64:315-322.)

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“…Excessive deposition of extracellular matrix (ECM) in heart failure directly restricts normal ventricular function by reducing wall compliance; it also reduces diffusion efficiency, promotes arrhythmia, and possibly limits regenerative efforts of cardiomyocytes (2)(3)(4). Progressive cardiac fibrosis in heart failure is predominantly mediated by the tissue-resident cardiac fibroblast, which becomes activated and then differentiated into a cell type referred to as the myofibroblast (5,6).…”

Section: Introductionmentioning

confidence: 99%

Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis

Khalil¹,

Kanisicak²,

Prasad³

et al. 2017

Journal of Clinical Investigation

704

551

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reverse transcribed using random oligo-dT primers and a Verso cDNA Synthesis Kit (Thermo Fisher, AB1453) according to the manufacturer's instructions. Real-time PCR was performed using SsoAdvanced SYBR Green (Bio-Rad, 6090), and Rpl7 expression was used for normalization. The following primer sets were used to identify transcripts: collagen 1a1, 5′-AATGGCACGGCTGTGTGCGA and 5′-AACGGGTCCCCTTG-GGCCTT; collagen 3a1, 5′-TCCCCTGGAATCTGTGAATC and 5′-TGAGTCGAATTGGGGAGAAT; periostin, 5′-ACGGAGCTCAGG-GCTGAAGATG and 5′-GTTTGGGCCCTGATCCCGAC.Cell death analysis. At 90% confluence, primary skin fibroblasts were treated with 200 nM staurosporine for 36 hours or vehicle (DMSO). Cell death was determined by the Muse Count & Viability Assay (Millipore, MCH100102) as previously described (62). Briefly, the medium was collected with the trypsin-liberated cells, which were centrifuged and washed twice with PBS and then incubated with the Muse Count & Viability reagent. The cells were then quantified on a Muse cell analyzer (Millipore) at 5,000 counts per sample.Statistics. One-way ANOVA with post hoc Tukey's honest significant difference (HSD) or Student's t test was used to determine statistical significance, depending on the type of data analyzed and number of comparisons. P values of less than 0.05 were considered statistically significant. Averaged data are presented with SEM to indicate variability.Study approval. Mice were observed daily and cages changed weekly by certified veterinary technicians at Cincinnati Children's Hospital Medical Center. Mice were also closely assessed for their well-being, monitored by adequate physical activity and food intake on a daily basis. Housing conditions and husbandry conformed to AAALAC standards as well as the standard guidelines from the NIH Office of Laboratory Animal Welfare (http://grants.nih.gov/grants/olaw/animal_use. htm). The institution also retains ongoing certification by AAALAC.

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Pathological Ventricular Remodeling

Cited by 136 publications

References 106 publications

T1 Mapping in Characterizing Myocardial Disease

T1 Mapping in Characterizing Myocardial Disease

Serelaxin Is a More Efficacious Antifibrotic Than Enalapril in an Experimental Model of Heart Disease

Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis

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