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

Kuusisto J, Kärjä V, Sipola P, Kholová I, Peuhkurinen K, Jääskeläinen P, Naukkarinen A, Ylä-Herttuala S, Punnonen K, Laakso M - Heart (2012)

Bottom Line: Endomyocardial biopsy samples taken from the patients with HCM were compared with matched myocardial autopsy specimens.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.

View Article: PubMed Central - PubMed

Affiliation: Kuopio University Hospital, Department of Medicine/Center for Medicine and Clinical Research, Puijonlaaksontie 2, Finland. johanna.kuusisto@kuh.fi

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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(A) Typical histopathology in an endomyocardial biopsy of a patient with hypertrophic cardiomyopathy (HCM). (a) A general view, haematoxylin and eosin (H&E) ×200; (b, c) moderate fibre disarray, interstitial fibrosis (asterisk), moderate myocyte size heterogeneity and hypertrophy and scattered mononuclear inflammatory cells (arrows), H&E ×400, ×630. (B) Mild histopathological findings in a patient with HCM. (a) A general view, H&E ×200; (b, c) mild fibre disarray, fibrosis (asterisk), myocyte hypertrophy and occasional mononuclear inflammatory cells (arrow), H&E ×400, ×630. (C) Severe HCM. (a) A general view: Weigert van Gieson staining highlights marked fibrosis (red, shown by asterisk), ×200; (b) multiple mononuclear inflammatory cells (arrow); (C) showing CD3 positivity in immunohistochemistry (staining in brown, arrow). Original magnification ×400. The patient had severe symptoms, marked left ventricular hypertrophy and inducible ventricular arrhythmia in ventricular stimulation. An intracardiac defibrillator was subsequently implanted.
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fig2: (A) Typical histopathology in an endomyocardial biopsy of a patient with hypertrophic cardiomyopathy (HCM). (a) A general view, haematoxylin and eosin (H&E) ×200; (b, c) moderate fibre disarray, interstitial fibrosis (asterisk), moderate myocyte size heterogeneity and hypertrophy and scattered mononuclear inflammatory cells (arrows), H&E ×400, ×630. (B) Mild histopathological findings in a patient with HCM. (a) A general view, H&E ×200; (b, c) mild fibre disarray, fibrosis (asterisk), myocyte hypertrophy and occasional mononuclear inflammatory cells (arrow), H&E ×400, ×630. (C) Severe HCM. (a) A general view: Weigert van Gieson staining highlights marked fibrosis (red, shown by asterisk), ×200; (b) multiple mononuclear inflammatory cells (arrow); (C) showing CD3 positivity in immunohistochemistry (staining in brown, arrow). Original magnification ×400. The patient had severe symptoms, marked left ventricular hypertrophy and inducible ventricular arrhythmia in ventricular stimulation. An intracardiac defibrillator was subsequently implanted.

Mentions: Table 2 shows the histopathological findings in haematoxylin–eosin stained endomyocardial samples in patients with HCM. Sufficient endomyocardial biopsy samples for histology were available for 16 of 20 patients with HCM. Histological samples showed variable amounts of heterogeneity of myocyte size, myocyte hypertrophy, myofibre disarray, myocardial fibrosis, inflammatory cell infiltration and intramyocardial small artery narrowing. Interstitial and perivascular fibrosis was found in about 90% of cases. Inflammatory cell infiltration, including mainly mononuclear inflammatory cells and eosinophilic granulocytes, was found in 37% of the patients. Narrowed intramyocardial small arteries were found in one-quarter of the patients. Figure 2 A–C shows typical, mild and marked histopathological findings in patients with HCM, respectively.


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

Kuusisto J, Kärjä V, Sipola P, Kholová I, Peuhkurinen K, Jääskeläinen P, Naukkarinen A, Ylä-Herttuala S, Punnonen K, Laakso M - Heart (2012)

(A) Typical histopathology in an endomyocardial biopsy of a patient with hypertrophic cardiomyopathy (HCM). (a) A general view, haematoxylin and eosin (H&E) ×200; (b, c) moderate fibre disarray, interstitial fibrosis (asterisk), moderate myocyte size heterogeneity and hypertrophy and scattered mononuclear inflammatory cells (arrows), H&E ×400, ×630. (B) Mild histopathological findings in a patient with HCM. (a) A general view, H&E ×200; (b, c) mild fibre disarray, fibrosis (asterisk), myocyte hypertrophy and occasional mononuclear inflammatory cells (arrow), H&E ×400, ×630. (C) Severe HCM. (a) A general view: Weigert van Gieson staining highlights marked fibrosis (red, shown by asterisk), ×200; (b) multiple mononuclear inflammatory cells (arrow); (C) showing CD3 positivity in immunohistochemistry (staining in brown, arrow). Original magnification ×400. The patient had severe symptoms, marked left ventricular hypertrophy and inducible ventricular arrhythmia in ventricular stimulation. An intracardiac defibrillator was subsequently implanted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3368494&req=5

fig2: (A) Typical histopathology in an endomyocardial biopsy of a patient with hypertrophic cardiomyopathy (HCM). (a) A general view, haematoxylin and eosin (H&E) ×200; (b, c) moderate fibre disarray, interstitial fibrosis (asterisk), moderate myocyte size heterogeneity and hypertrophy and scattered mononuclear inflammatory cells (arrows), H&E ×400, ×630. (B) Mild histopathological findings in a patient with HCM. (a) A general view, H&E ×200; (b, c) mild fibre disarray, fibrosis (asterisk), myocyte hypertrophy and occasional mononuclear inflammatory cells (arrow), H&E ×400, ×630. (C) Severe HCM. (a) A general view: Weigert van Gieson staining highlights marked fibrosis (red, shown by asterisk), ×200; (b) multiple mononuclear inflammatory cells (arrow); (C) showing CD3 positivity in immunohistochemistry (staining in brown, arrow). Original magnification ×400. The patient had severe symptoms, marked left ventricular hypertrophy and inducible ventricular arrhythmia in ventricular stimulation. An intracardiac defibrillator was subsequently implanted.
Mentions: Table 2 shows the histopathological findings in haematoxylin–eosin stained endomyocardial samples in patients with HCM. Sufficient endomyocardial biopsy samples for histology were available for 16 of 20 patients with HCM. Histological samples showed variable amounts of heterogeneity of myocyte size, myocyte hypertrophy, myofibre disarray, myocardial fibrosis, inflammatory cell infiltration and intramyocardial small artery narrowing. Interstitial and perivascular fibrosis was found in about 90% of cases. Inflammatory cell infiltration, including mainly mononuclear inflammatory cells and eosinophilic granulocytes, was found in 37% of the patients. Narrowed intramyocardial small arteries were found in one-quarter of the patients. Figure 2 A–C shows typical, mild and marked histopathological findings in patients with HCM, respectively.

Bottom Line: Endomyocardial biopsy samples taken from the patients with HCM were compared with matched myocardial autopsy specimens.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.

View Article: PubMed Central - PubMed

Affiliation: Kuopio University Hospital, Department of Medicine/Center for Medicine and Clinical Research, Puijonlaaksontie 2, Finland. johanna.kuusisto@kuh.fi

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.

Show MeSH
Related in: MedlinePlus