Myocardial hypertrophy, fibrosis and infarction following exposure of the heart to radiation for Hodgkin's disease

O’Donnell, L.; O'Neill, Terence W; Toner, Mary; O’Briain, S.; Graham, Ian

doi:10.1136/pgmj.62.733.1055

Cited by 11 publications

(5 citation statements)

References 13 publications

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“…Premature coronary heart disease, electrical conduct defects or valve abnormalities are often associated with RIHD (4–6). In the early phase, RIHD often presents as heart failure with preserved ejection fraction (HFpEF), characterized by LVH and diastolic dysfunction (1, 7, 8). Radiotherapy significantly improves cancer patient survival; however, in the long-term, patients are at risk of RIHD and subsequent heart failure which becomes a major health issue affecting outcome, quality of life and health care costs (1).…”

Section: Introductionmentioning

confidence: 99%

Selective Heart Irradiation Induces Cardiac Overexpression of the Pro-hypertrophic miR-212

et al. 2019

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Background: A deleterious, late-onset side effect of thoracic radiotherapy is the development of radiation-induced heart disease (RIHD). It covers a spectrum of cardiac pathology including also heart failure with preserved ejection fraction (HFpEF) characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction. MicroRNA-212 (miR-212) is a crucial regulator of pathologic LVH via FOXO3-mediated pathways in pressure-overload-induced heart failure. We aimed to investigate whether miR-212 and its selected hypertrophy-associated targets play a role in the development of RIHD. Methods: RIHD was induced by selective heart irradiation (50 Gy) in a clinically relevant rat model. One, three, and nineteen weeks after selective heart irradiation, transthoracic echocardiography was performed to monitor cardiac morphology and function. Cardiomyocyte hypertrophy and fibrosis were assessed by histology at week 19. qRT-PCR was performed to measure the gene expression changes of miR-212 and forkhead box O3 (FOXO3) in all follow-up time points. The cardiac transcript level of other selected hypertrophy-associated targets of miR-212 including extracellular signal-regulated kinase 2 (ERK2), myocyte enhancer factor 2a (MEF2a), AMP-activated protein kinase, (AMPK), heat shock protein 40 (HSP40), sirtuin 1, (SIRT1), calcineurin A-alpha and phosphatase and tensin homolog (PTEN) were also measured at week 19. Cardiac expression of FOXO3 and phospho-FOXO3 were investigated at the protein level by Western blot at week 19. Results: In RIHD, diastolic dysfunction was present at every time point. Septal hypertrophy developed at week 3 and a marked LVH with interstitial fibrosis developed at week 19 in the irradiated hearts. In RIHD, cardiac miR-212 was overexpressed at week 3 and 19, and FOXO3 was repressed at the mRNA level only at week 19. In contrast, the total FOXO3 protein level failed to decrease in response to heart irradiation at week 19. Other selected hypertrophy-associated target genes failed to change at the mRNA level in RIHD at week 19. Conclusions: LVH in RIHD was associated with cardiac overexpression of miR-212. However, miR-212 seems to play a role in the development of LVH via FOXO3-independent mechanisms in RIHD. As a central regulator of pathologic remodeling, miR-212 might become a novel target for RIHD-induced LVH and heart failure.

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Section: Introductionmentioning

confidence: 99%

Selective Heart Irradiation Induces Cardiac Overexpression of the Pro-hypertrophic miR-212

et al. 2019

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“…Late cardiac damage following RT appears to result from injury to vascular endothelial cells, leading to tissue necrosis, capillary rupture, and/or micro thrombi 10 . Damage to the microvasculature then leads to myocardial ischemia and fibrosis 11 .…”

Section: Introductionmentioning

confidence: 99%

Uncomplicated Tumour Control Probability (UTCP) in post-operative radiotherapy of left breast cancer- three dimensional conformal versus Intensity Modulated Radiation Therapy (IMRT )

El-Mesidy¹,

El-Kashif²,

Sherbini³

et al. 2012

Kasr-Al-Aini J.of Clin. Onc. and Nuc. Med.

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Purpose:To compare calculated tumour control probability (TCP) of the target(s) and normal tissue complication probability (NTCP) for Organs At Risk (OAR); lungs, heart, and contralateral breast using 3D conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) in patients with operable left breast cancer. Uncomplicated Tumour Control Probability (UTCP) was accordingly calculated. Patients and Methods: Sixty female patients with operable left breast cancer either post mastectomy or breast conservative surgery (BCS) underwent 3D-CRT and IMRT planning. Target coverage and target dose distribution as well as doses received by OAR (lungs, heart) were evaluated in both techniques. The TCP for target volumes, the NTCP for late excess cardiac mortality and radiation pneumonitis using Burman model. UTCP for each target was also calculated by subtracting the sum of NTCPs for OAR from TCP of the each target conclusion: UTCP was significantly better in the IMRT arm in both left breast & chest wall targets either IMC was included in the target or not .

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“…RT-induced cardiomyopathy and HF cover a spectrum of functional abnormalities. Among them, a typical initial phase is HFpEF characterized by DD and compensatory LVH [ 29 , 30 , 31 ]. Later on, due to the progression of interstitial fibrosis and loss of cardiomyocytes, the clinical entity of HFrEF develops [ 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease

Kovács

Varga

et al. 2021

IJMS

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Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-β/SMAD signaling pathway in our RIHD model.

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Myocardial hypertrophy, fibrosis and infarction following exposure of the heart to radiation for Hodgkin's disease

Cited by 11 publications

References 13 publications

Selective Heart Irradiation Induces Cardiac Overexpression of the Pro-hypertrophic miR-212

Selective Heart Irradiation Induces Cardiac Overexpression of the Pro-hypertrophic miR-212

Uncomplicated Tumour Control Probability (UTCP) in post-operative radiotherapy of left breast cancer- three dimensional conformal versus Intensity Modulated Radiation Therapy (IMRT )

Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease

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