Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy

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Abstract

Objective

To investigate the role of inflammation in the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy (HCM).

Design

Clinical study.

Setting

Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.

Subjects

Twenty-four patients with a single HCM-causing mutation D175N in the α-tropomyosin gene and 17 control subjects.

Main outcome measures

Endomyocardial biopsy samples taken from the patients with HCM were compared with matched myocardial autopsy specimens. Levels of high-sensitivity C-reactive protein (hsCRP) and proinflammatory cytokines were measured in patients and controls. Myocardial late gadolinium enhancement (LGE) in cardiac MRI (CMRI) was detected.

Results

Endomyocardial samples in patients with HCM showed variable myocyte hypertrophy and size heterogeneity, myofibre disarray, fibrosis, inflammatory cell infiltration and nuclear factor kappa B (NF-κB) activation. Levels of hsCRP and interleukins (IL-1β, IL-1RA, IL-6, IL-10) were significantly higher in patients with HCM than in control subjects. In patients with HCM, there was a significant association between the degree of myocardial inflammatory cell infiltration, fibrosis in histopathological samples and myocardial LGE in CMRI. Levels of hsCRP were significantly associated with histopathological myocardial fibrosis. hsCRP, tumour necrosis factor α and IL-1RA levels had significant correlations with LGE in CMRI.

Conclusions

A variable myocardial and systemic inflammatory response was demonstrated in patients with HCM attributable to an identified sarcometric mutation. Inflammatory response was associated with myocardial fibrosis, suggesting that myocardial fibrosis in HCM is an active process modified by an inflammatory response.

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Most cited references 26

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Hypertrophic cardiomyopathy: a systematic review.

Barry J Maron (2002)

Throughout the past 40 years, a vast and sometimes contradictory literature has accumulated regarding hypertrophic cardiomyopathy (HCM), a genetic cardiac disease caused by a variety of mutations in genes encoding sarcomeric proteins and characterized by a broad and expanding clinical spectrum. To clarify and summarize the relevant clinical issues and to profile rapidly evolving concepts regarding HCM. Systematic analysis of the relevant HCM literature, accessed through MEDLINE (1966-2000), bibliographies, and interactions with investigators. Diverse information was assimilated into a rigorous and objective contemporary description of HCM, affording greatest weight to prospective, controlled, and evidence-based studies. Hypertrophic cardiomyopathy is a relatively common genetic cardiac disease (1:500 in the general population) that is heterogeneous with respect to disease-causing mutations, presentation, prognosis, and treatment strategies. Visibility attached to HCM relates largely to its recognition as the most common cause of sudden death in the young (including competitive athletes). Clinical diagnosis is by 2-dimensional echocardiographic identification of otherwise unexplained left ventricular wall thickening in the presence of a nondilated cavity. Overall, HCM confers an annual mortality rate of about 1% and in most patients is compatible with little or no disability and normal life expectancy. Subsets with higher mortality or morbidity are linked to the complications of sudden death, progressive heart failure, and atrial fibrillation with embolic stroke. Treatment strategies depend on appropriate patient selection, including drug treatment for exertional dyspnea (beta-blockers, verapamil, disopyramide) and the septal myotomy-myectomy operation, which is the standard of care for severe refractory symptoms associated with marked outflow obstruction; alcohol septal ablation and pacing are alternatives to surgery for selected patients. High-risk patients may be treated effectively for sudden death prevention with the implantable cardioverter-defibrillator. Substantial understanding has evolved regarding the epidemiology and clinical course of HCM, as well as novel treatment strategies that may alter its natural history. An appreciation that HCM, although an important cause of death and disability at all ages, does not invariably convey ominous prognosis and is compatible with normal longevity should dictate a large measure of reassurance for many patients.

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Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future

Douglas L. Mann (2002)

Recent studies have identified the importance of proinflammatory mediators in the development and progression of heart failure. The growing appreciation of the pathophysiological consequences of sustained expression of proinflammatory mediators in preclinical and clinical heart failure models culminated in a series of multicenter clinical trials that used “targeted” approaches to neutralize tumor necrosis factor in patients with moderate to advanced heart failure. However, these targeted approaches have resulted in worsening heart failure, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. This review will summarize the tremendous growth of knowledge that has taken place in this field, with a focus on what we have learned from the negative clinical trials, as well as the potential direction of future research in this area.

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The histologic basis of late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

Mary Sheppard, Andrew Elkington, Margaret Burke … (2004)

We sought to identify the histologic basis of myocardial late gadolinium enhancement cardiovascular magnetic resonance (CMR) in hypertrophic cardiomyopathy (HCM). The histologic basis of late gadolinium CMR in patients with HCM is unknown. A 28-year-old male patient with HCM and heart failure underwent late gadolinium enhancement CMR and, 49 days later, heart transplantation. The explanted heart was examined histologically for the extent of collagen and disarray, and the results were compared with a previous in vivo CMR scan. Overall, 19% of the myocardium was collagen, but the amount per segment varied widely (SD +/- 19, range 0% to 71%). Both disarray and collagen were more likely to be found in the mesocardium than in the endo- or epicardium. There was a significant relationship between the extent of late gadolinium enhancement and collagen (r = 0.7, p 15% collagen were more likely to have late gadolinium enhancement. Regional wall motion was inversely related to the extent of myocardial collagen and late gadolinium enhancement but not disarray (p = 0.0003, 0.04, and NS, respectively). In this patient with HCM and heart failure, regions of myocardial late gadolinium enhancement by CMR represented regions of increased myocardial collagen but not disarray.

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Author and article information

Journal

Journal ID (nlm-ta): Heart

Journal ID (iso-abbrev): Heart

Journal ID (publisher-id): heart

Journal ID (hwp): heartjnl

Title: Heart

Publisher: BMJ Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 1355-6037

ISSN (Electronic): 1468-201X

Publication date (Electronic): 24 March 2012

Publication date (Print): 1 July 2012

Publication date PMC-release: 24 March 2012

Volume: 98

Issue: 13

Pages: 1007-1013

Affiliations

[1 ]Department of Medicine, Kuopio University Hospital, Kuopio, Finland

[2 ]Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland

[3 ]Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland

[4 ]A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland

[5 ]Laboratory Center of Eastern Finland, Kuopio, Finland

[6 ]University of Eastern Finland, Kuopio, Finland

Author notes

Correspondence to Professor Johanna Kuusisto, Kuopio University Hospital, Department of Medicine/Center for Medicine and Clinical Research, Puijonlaaksontie 2, PO Box 1777, Kuopio FIN-70210, Finland; johanna.kuusisto@ 123456kuh.fi

See Editorial, p [Related article:]965

VK, PS contributed equally.

Article

Publisher ID: heartjnl-2011-300960

DOI: 10.1136/heartjnl-2011-300960

PMC ID: 3368494

PubMed ID: 22447464

SO-VID: a373e59c-abd2-4223-86e6-5d72385065ec

Copyright © © 2012, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

History

Date accepted : 17 January 2012

Custom metadata

special-feature editors-choice

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: inflammation,coronary artery disease,hypertrophic cardiomyopathy,fibrosis,coronary angioplasty,hcm,mri,myocardial perfusion,myocardial function,late gadolinium enhancement,invasive cardiology,aortic stenosis,cardiomyopathy hypertrophic,tissue characters,myocardial infarction,endocrinology,myocardial ischaemia,arrhythmias,genetics

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: inflammation, coronary artery disease, hypertrophic cardiomyopathy, fibrosis, coronary angioplasty, hcm, mri, myocardial perfusion, myocardial function, late gadolinium enhancement, invasive cardiology, aortic stenosis, cardiomyopathy hypertrophic, tissue characters, myocardial infarction, endocrinology, myocardial ischaemia, arrhythmias, genetics

Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy

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Abstract

Objective

Design

Setting

Subjects

Main outcome measures

Results

Conclusions

Related collections

Cardiovascular Innovations and Applications

Most cited references 26

Hypertrophic cardiomyopathy: a systematic review.

Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future

The histologic basis of late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

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