Introduction
Clinical manifestations of RIHD
Acute forms of RIHD
Acute pericarditis
Acute conduction system abnormalities
Chronic forms of RIHD
Chronic pericarditis
Ischemic heart disease (IHD)
Type of study | Radiotherapy era and number of cases | Dosimetry data | Related risk | Dosimetry data | Related risk | Effect of age | Effect of CAD risk factors | Refs. |
---|---|---|---|---|---|---|---|---|
Population-based case–control study endpoint: major coronary event* | Stockholm 1958–2002 Denmark 1977–2007 n = 963 cases | MHD = 1 Gy increase | ERR = 7.4% | MHD = 2 Gy MHD = 2–4 Gy MHD = 5–9 Gy MHD ≥ 10 Gy | 10% (95% CI, − 9–33), 30% (95% CI, 14–49), 40% (95% CI, 15–72), | Not reported | ERR(IHD) = 6.67 (ERR<10yrs = 13.43 ERR>10 yrs = 2.09) ERR(other) = 1.96 (ERR<10yrs = 2.60 ERR>10 yrs = 1.63) | [8] |
Cohort study endpoint:acute coronary event | 2005–2008 n = 910 breast cancer patients | MHD = 1 Gy increase | Cumulative incidence = 16.5% | LV-V5 = 1 Gy increase | HR = 1.017 | Increased with age | Increased with their presence | [27] |
Nested case–control study, endpoint: AMI | 1970–2009 n = 183 cases (median MHD: 8.9 Gy) | MHD = 1 Gy increase | ERR = 6.4% | MHD > 20 Gy | 3.4 × increased risk | ERR<45 yrs = 24.2%/Gy, ERR≥50 yrs = 2.5%/Gy | ERR1 1 risk factor = 1.86 | [15] |
Retrospective chort study endpoint: OS | 1998–2012 Mayo Clinic, n = 76 pts with breast, lung, mediastinum, GI tumors, RT and cardiac stenting | MHD (Gy) | HR (Cox multivariate analysis) = 1.05 (95% CI 1.02–1.08) | ACEI/ARB use | HR (Cox multivariate analysis) = 3.04 (95% CI 1.28–7.19) | None in multivariate analysis | None in multivariate analysis | [26] |
Nested case–control endpoint: CAD | 1965–1995 n = 325 HML cases | MHD = 1 Gy increase | ERR = 7.4% | MHD = 20 Gy | 2.5 × increased risk | ERR<27.5yrs = 20.0% ERR27.5–36.4yrs = 8.8% ERR36.5–50.9 yrs = 4.2%; | ERR1 risk factor = 1.5 ERRphysical activity = 0.5 | [9] |
Cardiomyopathy and heart failure (HF)
Valvular heart disease (VHD)
Chronic conduction system abnormalities
Pathomechanisms of RIHD
Pathomechanisms in the acute phase of RIHD
Mechanisms of increased oxidative/nitrosative/nitrative stress in the acute phase of RIHD
Endothelial cell injury and acute inflammation in RIHD
Increased thrombogenicity and acute inflammation in RIHD
Endoplasmic reticulum stress and apoptosis in RIHD
Necrosis in RIHD
Autophagy in RIHD
Pathomechanisms in the chronic phase of RIHD
Mechanisms of the increased oxidative/nitrosative/nitrative stress in the chronic phase of RIHD
The interplay of oxidative/nitrosative/nitrative stress with chronic inflammatory pathways in RIHD
Compensatory cardiac hypertrophy in RIHD
Cardiac fibrosis in RIHD
Cellular senescence in RIHD
Diagnosis and follow-up of RIHD in patients
Prevention and therapy of RIHD
Prevention of RIHD by cardiac dose-sparing techniques
Prevention and therapy of RIHD with pharmacological agents
Anti-oxidants
Mode of action | Pharmacon(s) | Route of administration and dose | Timing of pharmacological treatment | FUP time after RT | Protective effects of pharmacons | Animal model of RIHD | Age/BW at start of experiment | RT dose (Gy) | Type of RT | Refs. |
---|---|---|---|---|---|---|---|---|---|---|
Antioxidants | Tocotrienols | Per os 230 mg/kg/ | Start: 24 h before RT (single dose) | 2 or 28 wk | ↓ Bax/Bcl2 (both FUP times) ↓ mPTP opening (2 wk) No effect on remodeling (28 wk) | Male ratsSD rats | 250–290 g | 21 Gy | Local heart irradiation | [111] |
Antioxidants | Pentoxifylline + α-tocopherol | Per os 100 mg/kg/d + per os 20 IU/kg/d | Start: 1 wk before RT or 3 mo after RT end: 6 mo | 6 mo | In both timing: ↓ LV diastolic pressure, ↓ Col-I and Col-III deposition | Male SD rats | 180–200 g | 5 × 9 Gy daily | Local heart irradiation | [93] |
Antioxidants | Pentoxifylline + α-tocopherol | ip. 15 mg/kg/d + ip. 5.5 mg/kg/d | Start: 3 days before RT end: 12 or 24 wk | 24 wk | Only after 24 wk treatment: ↓ cardiac TGF-β1 (mRNA) ↓ Cardiac fibrosis | Male SD rats | 12–14 wk | 20 Gy | Local heart irradiation | [112] |
Antioxidants | Pentoxifylline alone or with tocotrienols (containing α-tocopherol) | Per os 95–110 mg/kg/d ± per os 43 mg/kg/d (15–17 mg/kg/d) | Start: 3 mo after RT end: 6 mo | 6 mo | ↓Cardiac inflammatory infiltration: ↓ Mast cells and macrophages | Male SD rats | 220–260 g | 21 Gy | Local heart irradiation | [113] |
Antioxidants | amifostine | ip. 200 mg/kg (single dose) | Start: 20–30 min before RT | 24 hor 100 d | After 100 d: ↓ Myocardial degeneration (focal vacuolization) | MaleWistar rats | 12–14 wk (240–260 g) | 15 Gy | Local heart irradiation | [117] |
Antioxidants | amifostine | ip. 200 mg/kg (single dose) | Start: 30 min before RT | 6 mo | ↓ Vascular injury ↓ vasculitis | Male Wistar rats | 10–12 wk (200–250 g) | 18 Gy | Local heart irradiation | [114] |
Antioxidants | amifostine | ip. 160 mg/kg (single dose) | Start: 15–20 min before RT | 6 mo | in the 22.5 Gy group: maintained cardiac output ↓ Ventricular fibrosis | Female SD rats | 12 wk old | 15, 20 or 22.5 Gy | Local heart irradiation | [118] |
Steroidal anti-inflammatory drugs | Dexamethasone | iv. 0.5 mg/d | 2 h before RT and identical dose every 24 h for 3 d | 24 h or 100 d | ↓ Cardiac OH-Pro content ↓ Cardiac fibrosis | Male New Zealand rabbits | 2.2–2.6 kg | 20 Gy | Local heart irradiation | [121] |
Steroidal anti-inflammatory drugs | Methylprednisolone | iv. 30 mg/kg | 2 h before RT and then twice daily for 3 d | 100 d | ↑ Survival ↓ Cardiac OH-Pro content ↓ Cardiac fibrosis ↓ Pericarditis and pericardial effusion | MaleNew Zealand rabbits | 1.8–2.4 kg | 20 Gy | Local heart irradiation | [122] |
Non-steroidal anti-inflammatory drugs | Ibuprofen | iv. 12.5 mg/kg | 2 h before RT and then twice daily for 2 d | 100 d | ↑ Survival ↓ Cardiac OH-Pro content ↓ Cardiac fibrosis ↓ Pericarditis and pericardial effusion | Male New Zealand rabbits | 1.8–2.4 kg | 20 Gy | Local heart irradiation | [122] |
Cardioprotective drugs | Trimetazidine | Per os 10 or 20 mg/kg/d | Start: 1 wk before or 1 wk after RT end: 8 wk | 8 wk | ↓ Fibrosis via the CTGF/TGF-β1/Smad pathway | Male C57BL6 mice | 8 wk (18–22 g) | 20 Gy | Thoracic irradiation | [127] |
Cardioprotective drugs | GHRH and its agonistic analouges (JI-34 and MR-356) | 1,10, 50, 100 or 500 nM | Start: after RT | 48 h | ↑ Viablity ↓ ROS level ↓ Activity of RISK/SAFE pathway (only JI-34) | neonatal rat cardiomyocytes | – | 10 Gy | – | [134] |
Statins | Lovastatin | Per os 10 mg/kg | Pre-treatment only 48 h and 24 h before RT | 4–24 h or 3 wk | ↓ Cardiac expression of NF-KB ↓ Cell adhesion molecules ↓ Pro-inflammatory markers ↓ Pro-fibrotic markersin a time-dependent manner | Female Blb/c mice | 3–4 mo (25 g) | 6 Gy or 2 × 2.5 Gy | TBI | [141] |
Statins | Atorvastatin | Per os 0.25 mg/d | Start: 1 d before RT end: 6 wk | 6 wk | ↓ LV conexin-43 ↓ LV PKCε ↓ LV miR-21 | MaleWistar rats | 3 mo | 25 Gy | Local heart irradiation | [138] |
Statins | Atorvastatin | 10 or 20 mg/kg/d | Start: 12 wk before RT or from first d after RT end: 12 wk | 12 wk | ↑ EF and FS ↓ cardiac fibrosis via the TGF-b1/Smad3, RhoA/ROCK, and PI3K/AKT pathways | Male SD rats | 11–14 wk | 7 × 3 Gy | Local heart irradiation | [142] |
RAAS inhibitors | Captopril | Per os 30–60 mg/kg/d | Start: first day after RT end: 3 mo | 3 mo | ↓ LVEDP ↓ Pericardial fibrosis ↓ Cardiac fibrosis | Male Wistar rats | – | 20 Gy | Local heart irradiation | [144] |
RAAS inhibitors | captopril or enalapril or fosinopril | Per os 145–207 mg/m2/d per os 19–28 mg/m2/d per os 19–28 mg/m2/d | Start: 1 wk after RT end: 7 mo | 7 mo | ↓ Pulmonary collagen synthesis | Female WAG/RijCmcr rats | 9–10 wk | 13 Gy | Thoracic irradiation | [145] |
Novel pharmaceutical agents | rhNRG-1β | iv. 15 μg/kg | 3 d before RT + 7 d after RT | 20 wk | ↑ FS ↑ Mitochondrial function ↓ Cardiac fibrosis via the ErbB2-ERK SIRT1 pathway | Male Sprague–Dawley rats | 200–250 g | 21 Gy | Local heart irradiation | [151] |
Novel pharmaceutical agents | Ac-SDKP | sc. 3.2 mg/kg/d | Start: within 24 h after RT end: 18 wk | 18 wk | ↓ Inflammation ↓ Macrophage activation ↓ Fibrosis | Male and female SD rats | 10–12 wk | 30 Gy | Local chest irradiation | [156] |
Novel pharmaceutical agents | PACAP38 | ip. 10 µg/100 µl | Start: 2 h before RT + additional doses: 24 h and 48 h after RT | 21 days | ↓ Apoptosis ↓ Cardiac fibrosis | Male C57/BL6 mice | 6–8 wk (20–25 g) | 14 Gy | Thoracic irradiation | [159] |
Novel pharmaceutical agents | IPW-5371 (TGF-β1 receptor inhibitor) | Per os 10 or 30 mg/kg/d | Start: 24 h after RT end: 6 or 20 wk | 6 mo | ↑ Survival ↑ Cardiac function ↓ Cardiac fibrosis | Male and female C57L/J mice | 6–8 wk | 11.5 Gy | 5 Gy TBI + 6.5 Gy thoracic irradiation | [162] |