Radiation Associated Cardiac Disease

Magdy El-Masry
Prof. of Cardiology
Tanta University

Cancer and Treatment Modalities
CVD in cancer survivors
↓
Screening of cancer survivors

 Chest Radiotherapy is frequently used as an adjunct to surgery/chemotherapy in
thoracic malignancies (breast, lung, esophageal) and lymphomas.
 Although radiotherapy results in significantly improved survival of cancer patients,
the irradiation of healthy surrounding tissues results in complications.

Radiation Associated Cardiac Disease :
An Under-Recognized Entity?

Management Pearls
from a New Expert Review
JACC Scientific Expert Panel
( J Am Coll Cardiol 2019;74:905–27 )

JACC panel gives guidance on nuanced care
of a very complex disease

Cardiology
Cleveland
 Milind Y. Desai
 Brian P. Griffin
Switzerland
 Stephan Windecker
Belgium
 Patrizio Lancellotti
Netherlands
 Jeroen J. Bax
Radiation Oncology
New York
 Oren Cahlon
Cardiothoracic Surgery
Cleveland
 Douglas R. Johnston
The review, which was published by JACC on Aug.
2019 , is a consensus effort by an international
group of seven experts based on their experience
with RACD over the past 20 years.
The article covers a description of at-risk groups,
clinical manifestations, screening recommendations,
and management and surgical considerations.

Who is at Risk for RACD?
The review drew mostly on available data from patients who received radiation
therapy for breast cancer or Hodgkin’s lymphoma, although patients who have
received radiation for other cancers in the thorax are also at risk.
RACD
&
RAPD

 Age younger than 50 at time of radiation therapy
 Existing cardiovascular risk factors or disease
 Lack of shielding or cobalt as the radiation source
 High cumulative dose (>30 Gy) or
high dose of radiation fractions (>2 Gy/day)
 Tumor in or next to the heart
 Anterior or left chest radiation
 Concomitant chemotherapy, particularly with anthracyclines or trastuzumab
RACD
Risk factors for developing RACD

Mechanism of injury
Pro-inflammatory cytokines and chemokines (TNF-a, IL-6,
IL-8) ➔ chronic vascular damage
Fibroblasts ➔ activated myofibroblasts ➔ fibrosis
Altered DNA methylation ➔ changes in gene expression
Progressive valve thickening and calcification ➔ valve
regurgitation or stenosis
↑ Mitochondrial membrane permeability ➔ ↑ reactive
oxidative species ➔ chronic endothelial dysfunction
Suspected pathophysiology of radiation-induced cardiovascular damage.
Current Cardiology Reports (2020) 22:151
DNA, deoxyribonucleic acid; IL-6, interleukin 6; IL-8, interleukin 8; TNF-a, tumor necrosis factor-alpha.

 Incidence
 Time to onset
after acute radiation therapy

Cardiac structure Incidence
Myocardium 5-10%
Pericardium 8–30%
70% (autopsy studies)
Conduction system Up to 75%
Vasculopathy Up to 85%
Valves Up to 81%
(Symptoms in < 30% of those affected)
Cardiovascular complications of radiation therapy.
Journal of Nuclear Cardiology. Sept 10, 2020

Imaging or laboratory
abnormalities
Subclinical
Disease
Clinical
manifestations*
Clinical
Disease
Radiation-related
cardiac death
Mortality
RACD usually occurs with a certain latency from a few hours to several decades after the
heart and its substructures receive direct or indirect irradiation. According the occurrence
timing of cardiac radiation response, RACD includes acute and late cardiac toxicities.
*RACD comprises a spectrum of heart disease including cardiomyopathy, pericarditis,
coronary artery disease, valvular heart disease and conduction system abnormalities.

Overview of cardiovascular structures being affected after radiation therapy (RT)
Tissue Involved Diagnostic Consideration Time of Presentation After RT
Pericardium Acute pericarditis Days to weeks
Chronic effusion Weeks to months
Constrictive pericarditis Years
Vascular tree Premature CAD Years
MI Months to years
Asymptomatic CAD Years
Aortic arch calcification Years
Carotid stenosis Years
TIA/stroke Months to years
PVD Months to years
Endocardium Valvular disease Years
Myocardium Myocarditis Weeks to months
Cardiomyopathy Months to years
Chronic HF Years
Diastolic dysfunction Years
Conduction system Heart block Months to years
Clinical Cardiology. 2017;40:255–261.

Cardiac radiation exposure causes a number of abnormalities.
Exposure of the heart and surrounding vasculature to radiation may lead to several
adverse structural and functional changes in the heart (RACD)
Cancers 2020, 12(2), 415
Radiation Associated
Cardiac Disease (RACD)

“RACD can have diverse presentations that overlap with other
cardiac conditions,
and it may arise so long after the radiation exposure that clinicians
may not think of it,”
“But recognizing it is important, as management considerations
are paramount to a patient’s quality of life and long-term survival.”
Challenges of Clinical Detection for RACD

Potential manifestations of chest and mediastinal XRT
(J Am Coll Cardiol 2019;74:905–27)
Pericardium
•Constrictive pericarditis due to extensive fibrous thickening, adhesions, chronic constriction and can be associated with chronic pericardial
effusion. Associated with significantly higher surgical mortality
Cardiac muscle
•Diffuse subclinical myocardial fibrosis with associated progressive systolic and diastolic dysfunction
•Nonischemic cardiomyopathy can occur as an advanced stage of the disease due to extensive fibrosis with severe diastolic dysfunction and
signs and symptoms of heart failure (heart failure with preserved ejection fraction more common than reduced ejection fraction)
•Ischemic cardiomyopathy can occur due to advanced CAD
Valves
•Valve apparatus and leaflet thickening, fibrosis, shortening, and calcification predominant on left-sided valves
•Thickening and calcification of aortomitral curtain very commonly seen
•Valve regurgitation more common than stenosis
•Aortic valve stenosis most common stenotic lesion
Coronary artery disease
•Accelerated CAD often seen at a much younger age
•Concomitant atherosclerotic risk factors further enhance development of CAD
•Can occur ≤5 yrs after exposure
•Coronary ostia and proximal segments are typically involved
•CAD significantly increases the risk of myocardial infarction and death
Carotid artery disease
•Radiotherapy induced lesions are more extensive, involving longer segments and atypical areas of carotid segments
Other vascular disease
•Calcification of the ascending aorta and aortic arch (porcelain aorta)
•Lesions of any other vascular segments present within the radiation field
Conduction system disease
•Ectopy, tachyarrhythmia, baseline sinus tachycardia and autonomic dysfunction commonly seen
•Increased risk of pacemaker implantation due to conduction system disease
Lungs
•Progressive pulmonary fibrosis
•Recurrent pleural effusions

Pericardium
•Constrictive pericarditis due to extensive fibrous
thickening, adhesions, chronic constriction and can
be associated with chronic pericardial effusion.
Associated with significantly higher
surgical mortality
The final evolution,
constrictive pericarditis
The most frequent manifestation of acute stage
is exudative pericarditis

ECG and Echo showing pericarditis/pericardial effusion related to radiation therapy.
(A): ECG shows diffuse ST elevation suggestive of pericarditis. (B): Echo (subcostal view) showing small pericardial
effusion during attack of recurrence. (C): Echo (subcostal view) showing complete resolution of the pericardial effusion.
A 60 year female with left lung cancer, who presented in April 2014, within 2 weeks of radiation therapy with typical
pain of pericarditis. She had recurrence of pericarditis in Nov 14, for which she was given NSAID and cochicine with
good effect.Clinical Cardiology. 2017;40:255–261

Features of Pericardial Constriction
(A) Annulus reversus with preservation of septal early diastolic tissue velocity (e’), (B) compared with reduced lateral
wall e’; (C) reduced LV free wall strain due to tethering with reduced longitudinal motion (pink); (D) simultaneous
right and left heart catheterization shows equalization of diastolic pressures between the right and left
ventricles (black arrow); cardiac CT demonstrating pericardial calcification anteriorly (white arrow) and laterally
extending into the mitral annulus (yellow arrow) on (E) axial and (F) sagittal reconstructions. (J Am Coll Cardiol Img
2018;11:1132–49)

Cardiac muscle
•Diffuse subclinical myocardial fibrosis with
associated progressive systolic and diastolic
dysfunction
•Nonischemic cardiomyopathy can occur as an
advanced stage of the disease due to extensive
fibrosis with severe diastolic dysfunction and signs
and symptoms of heart failure
(HFpEF more common than HFrEF)
•Ischemic cardiomyopathy can occur due to
advanced CAD

Distinguishing Features of a Restrictive Cardiomyopathy
Due to Underlying Myocardial Fibrosis.
Reduced (A) septal and (B) lateral early diastolic tissue velocities (e’); (C) grade 3 restrictive mitral inflow, with a
short E-wave (white arrow) deceleration time (<150 ms) and small A-wave (yellow arrow); (D) reduced global 2D
longitudinal strain (pink region). (J Am Coll Cardiol Img 2018;11:1132–49)

Valves
•Valve apparatus and leaflet thickening, fibrosis,
shortening, and calcification predominant on left-
sided valves
•Thickening and calcification of aortomitral curtain
very commonly seen
•Valve regurgitation more common than stenosis
•Aortic valve stenosis most common stenotic lesion

Echo from a 52-year-old male treated with mantle radiation for Hodgkin’s lymphoma
25 years ago. PS-LAX view demonstrates severe, calcific stenosis of the aortic valve
(large arrow), with associated thickening and calcification of the aorto-mitral curtain
(small arrow). Curr Treat Options Cardio Med (2019) 21: 22

Echoshowing moderate arotic stenosis mild regurgitation. A 57 year old man with history of
Hodgkin’s lymphoma treated with mediastinal radiation in 1982. In February 2012 he was
evaluated because of symptoms of fatigue. Echo showed mild mitral annular calcification and
moderate calcific aortic stenosis.A cardiac catherization also showed CAD, with signficant
RCA disease for which he underwent stenting. (A): Echo (parasternal view) showing mild
mitral annular calcification and severe aortic valve calcification. (B): Doppler shows moderate
aortic stenosis with mild regurgitation. Clinical Cardiology. 2017;40:255–261

Latent Valvular Manifestations of Chest Radiation.
A 52-year-old man
treated with mantle
radiation for Hodgkin
lymphoma 25 years
ago demonstrates:
severe calcification of
the aortic valve,
aorto-mitral curtain,
and mitral valve on
2DE (A, arrows) and
CT(B, arrow), resulting
in severe
mitral (C) and
aortic (D) stenosis
using Doppler echo.
(J Am Coll Cardiol Img
2018;11:1132–49)

3 D – TEE demonstrating the difference between rheumatic valve disease and
radiation-induced valve disease.
(A) Rheumatic mitral valve with bilateral commissural fusion (black arrows).
(B) In contrast in radiation-induced valve disease, there is no commissural
fusion (red arrows). Gujral DM, et al. Heart 2015;0:1–8.

Coronary artery disease
•Accelerated CAD often seen at a much younger
age
•Concomitant atherosclerotic risk factors further
enhance development of CAD
•Can occur ≤5 yrs after exposure
•Coronary ostia and proximal segments are
typically involved
•CAD significantly increases the risk of myocardial
infarction and death

(A) Angiogram showing severe distal left main coronary stenosis extending into the
ostial and proximal LAD.
(B) IVUS of the distal left main confirming marked stenosis with circumferential
atherosclerosis without calcification.
JACC May 25, 2018

Radiation-Associated Coronary Artery Disease.
Severe right coronary ostial stenosis (arrows) after radiotherapy for Hodgkin lymphoma
(surgical clips from splenectomy). (J Am Coll Cardiol Img 2018;11:1132–49)

Example of radiation-associated ischemic disease.
c and d Diffuse multivessel CAD (white arrows) in middle-aged man previously treated with
thoracic radiotherapy for esophageal cancer presenting with acute coronary syndromes.
Current Cardiology Reports (2020) 22:151

Coronary artery calcium (CAC) imaging in an asymptomatic 73- year-old Caucasian female with a history of ductal
carcinoma in situ of the left breast, who received a total of 60.4 Gy radiation to the left breast with no adjunct
chemotherapy at the age of 64. The total CAC score was determined to be 320.2 with the CAC score of each coronary
vessel as follows: left main coronary artery = 171.1, left anterior descending artery = 126.1 (arrow), left circumflex = 0,
and right coronary artery = 22.9. Patient’s calcium burden places her in the 83rd percentile of coronary artery calcium
burden for age, race, and gender by the Multiethnic Study of Atherosclerosis (MESA)). Her estimated MESA 10-year
coronary heart disease (CHD) event rate is estimated to be 5.2 % if the CAC score is put into account and 2.6 % by
conventional risk factor assessment, showing the influence of the CAC score to increase her absolute risk of CHD events
at 10 years by 100 %. Curr Oncol Rep (2016) 18:15

Other vascular disease
•Calcification of the ascending aorta and aortic
arch (porcelain aorta)
•Lesions of any other vascular segments present
within the radiation field
Carotid artery disease
•Radiotherapy induced lesions are more
extensive, involving longer segments and atypical
areas of carotid segments

Radiation-Associated Aortic Disease
Severe calcification of the ascending aorta on cardiac CT (axial [A], coronal [B], and
sagittal [C] views; yellow arrows) and at the time of surgery (D) (white rrows).
*Calcification of the aorto-mitral curtain extending into the anterior mitral valve leaflet.
(J Am Coll Cardiol Img 2018;11:1132–49)

Conduction system disease
•Ectopy, tachyarrhythmia, baseline sinus
tachycardia and autonomic dysfunction* commonly
seen
•Increased risk of pacemaker implantation due to
conduction system disease**
*Inappropriate sinus tachycardia (IST)→risk of tachycardia-mediated cardiomyopathy
**XRT results in fibrosis of conduction pathways and subsequent abnormalities, including atrioventricular block, sick
sinus syndrome, atrial fibrillation, and ventricular tachyarrhythmias, that can occur years later . Infranodal and right
bundle branch blocks are common, with the anteriorly located right bundle being particularly susceptible. There is a
higher proportion of RACD patients who require pacemaker post-operatively

A 46-year-old man
(Hx of childhood radiotherapy for Hodgkin’s disease) → ECG showing complete heart block

A 46-year-old man (Hx of childhood radiotherapy for Hodgkin’s disease)
MRI of the heart showing
fibrosis (red arrows)
(A) Four chamber view. (B) Short axis view.
CT of the chest showing
calcification of the mitral valve
and no pulmonary pathology
TTE showing calcified
anterior mitral leaflet
( red arrow )
On arrival to the ER , he was bradycardic with mild SOB. ECG in ER showed CHB. Twenty
minutes later without any interventions, ECG showed sinus tachycardia with RBBB

Lungs
•Progressive pulmonary fibrosis
•Recurrent pleural effusions
Radiation-Induced Pulmonary Disease ( RAPD ) :
 An early reversible toxicity ( radation pneumonitis)
 A late irreversible toxicity (radiation fibrosis).
Radiation-induced pulmonary fibrosis
 is relatively common following chest radiotherapy
 is the late manifestation of radiation-induced pulmonary disease(RAPD)
 is another challenging aspect. (RACD + RAPD →make diagnosis particularly challenging)

51 year-old man treated with full mantle radiation for Hodgkin's lymphoma 20 years
ago demonstrates: a) severe calcification of the aortic valve, aorto-mitral curtain and
mitral valve on 2D echocardiography (left upper panel, arrows); b) increased
continuous flow Doppler gradient across the aortic valve suggesting severe stenosis
(left lower panel); c) increased continuous flow Doppler gradient across the mitral
valve suggesting severe stenosis (right upper panel) and computerized tomography
of the same patient demonstrating pulmonary fibrosis (arrow, right lower panel)
JACC :Jun 21, 2017
Pulmonary fibrosis
has an adverse
impact on survival
in RACD and should
be evaluated

The review recommends the following surveillance strategy
for patients who have a history of chest radiation therapy*:
Annual history and physical examination with a focus on signs and symptoms of RACD
> If signs and symptoms are present, testing as needed to evaluate
Screening echocardiography to assess structural abnormalities, ventricular performance
and valvular disease
> First time: Five years after exposure in high-risk patients, 10 years after exposure in
others
> Reassess every five years
Functional noninvasive stress testing to screen for coronary artery disease (CAD)
> First time: Five to 10 years after exposure in high-risk patients
> Reassess every five years
*? Baseline pre-radiotherapy ECHO & risk factor modification

Imaging modality Method Normal range Detection of cardiotoxcity Pro/con Recommendation
Echo, 2D LVEF,
biplane
Simpson
>53% ≥ 10% absolute change to
a value <50%
Widely accessible
and used, but
relatively high
variability
Recommended in
combination with
GLS and
biomarkers
Echo, speckle
tracking
GLS >18% value <18% or > 15%
relative reduction from
baseline
High reliability and
validity, sensitive for
early detection,
especially in
combination with
biomarkers.
Recommended in
combination with
2D echo and
biomarkers
Echo, 3D LVEF, 3D >55% ≥ 10% absolute change to
a value < 50%
High reliability, not
so widely used, more
complicated than 2D
Recommended if
available
CMR LVEF >55% ≥ 10% absolute change to
a value < 50%
Reliable method, low
availability, add
tissue information
when needed
Recommended
when tissue
information is
necessary (i.e.,
myocarditis)
Recommended imaging for detection and follow-up of cardiotoxicity in patients
treated for breast cancer.
Current Heart Failure Reports, September 2020
 Screening 2D echo .Consider GLS & 3D echo (( Baseline & Follow Up ))
 Alternative modality →CMR (Recommended in those with suboptimal echocardiography or discrepant results)

Myocardial perfusion study showing ischemia in the inferior wall (region of radiation therapy).
A 57 year old asymptomatic man, who had received a total of 50 Gy radiation 2 years
previously for cancer esophagus. Myocardial perfusion study shows ischemia in the inferior
wall. Clinical Cardiology. 2017;40:255–261
SPECT : a functional noninvasive stress test

 Specialized imaging plays a role to better evaluate RACD
and for preoperative assessment and planning.
 It should be assumed that patients suffered radiation injury
to the aorta, ventricles, pericardium, lungs and chest wall.
Journal of Nuclear Cardiology.
Sept 10, 2020

Tests to consider include:
Multidetector cardiac CT for preoperative evaluation and planning, to provide
full assessment of aortic, valvular and intravalvular calcium, and in some
instances noninvasive coronary angiography
Nuclear scintigraphy to assess myocardial ischemia
Cardiac MRI to assess myocardial fibrosis and pericardial constriction and as an
adjunct to echocardiography in some cases
Left and right heart catheterization with simultaneous pressure measurements
to distinguish constrictive pericarditis from myocardial restriction
Extracardiac vascular ultrasonography of the carotid and subclavian arteries
Pulmonary function testing

Challenge of Clinical Managements for RACD
Team Management , timing of surgery or transcatheter therapy
The review provides specific management guidance,
starting with the recommendation that patients be managed
by an experienced team of cardiologists, imaging specialists,
interventionalists and cardiothoracic surgeons.

Medical therapy should follow standard guidelines, as
no RACD-specific therapies have been identified and
validated.
However, most patients with significant symptoms
eventually require invasive therapies.

For RACD patients with CAD as the primary manifestation,
PCI is usually preferred unless concomitant valvular
disease can be addressed simultaneously with surgery.
Regarding transcatheter aortic valve replacement (TAVR), aortic
valve disease more frequently involves extensive calcification of
the valves and blood vessels, as well as severe conduction
abnormalities, posing potential complications.
With extensive planning, TAVR is still the preferred strategy for
severe isolated aortic stenosis in this setting, particularly if
transfemoral access can be safely employed.
“Careful evaluation of other valvular lesions needs to be undertaken, and if
there is evidence of advanced multivalvular disease (with or without
concomitant CAD), surgery might be the preferred option,”
“In terms of transcatheter mitral valve therapies, there needs to be further evolution
before their routine clinical implementation.”

Cardiac Surgery :
Issues of Concern
Quick In Quick Out

Preoperative preparation
“Significant radiation exposure is a critical risk factor that does not
show up on standard preoperative risk stratification scores,”
“For truly informed consent, these patients require more detailed
preoperative testing to better assess comorbidity, procedural risk
and optimal treatment strategies.”
Connect the dots

 The authors recommend that surgery generally be delayed to
later in the disease course than would be the case in the
absence of prior radiation therapy.
 Radiation injury to the lungs and pleura with resultant lymphatic
dysfunction makes patients susceptible to intrathoracic fluid
retention after surgery, significantly hampering recovery and
diminishing long-term quality of life.
 “Avoiding redo surgery should be a paramount consideration,”
“All issues, such as replacing multiple valves, should be taken
care of during the first operation if at all possible.”
(Redo surgery in RACD carries a significant ↑ in operative risk and mortality
compared with the non-RACD surgery)

 Thorough and systematic preoperative planning is critical, as is
flexibility in dealing with unexpected reconstruction problems,
 The authors specifically recommend an aggressive approach to
double-valve replacement because of the tendency of RACD
patients to have extensive calcification and a small aortic root and
mitral annulus.
 Because radiation-damaged valve tissue tends to thicken and scar
over time, replacement is preferred over repair, particularly for
the mitral valve.
 “Surgery for RACD often involves resection of extensive calcium
and reconstruction of multiple areas of the heart, including the
aorta and the annuli of the mitral and aortic valves,
Technically Challenging Operation → Commando Procedure .

Commando Procedure
(aortic and mitral valve replacement with reconstruction of aortomitral curtain)
(A) Aortic valve, mitral valve, and aorto-mitral curtain exposed and excised, (B) mitral
prosthesis implanted, (C) aorto-mitral curtain reconstructed using pericardium or synthetic
patch, (D) aortic valve prosthesis implantation, with patch reconstruction of the aortic
annulus, (E) ascending aortic patch closure. (J Am Coll Cardiol Img 2018;11:1132–49)

Echo revealing significant mixed (stenotic and regurgitant) aortic and mitral valve disease and calcification
of aortomitral curtain (A to C) Computed tomography revealing no porcelain aorta or pulmonary (D and
E) no obstructive coronary artery disease (F and G) schematic representation of Commando operation
(aortic and mitral valve replacement with reconstruction of aortomitral curtain) (H to K).
Patient With RACD Who Underwent Cardiac Surgery. ( J Am Coll Cardiol 2019;74:905–27 )

The article identified a number of postoperative
problems that tend to occur in this population:
1)Chronic pleural and pericardial effusions
2)Conduction system disturbances, often requiring longer
temporary pacing
3)Prolonged postoperative diuresis, sometimes for weeks
4)Fibrosis-induced limitation of cardiac output, requiring
avoidance of beta-blocker overuse and consideration of
higher pacemaker rates

Radiotherapy Protocols
Techniques to reduce radiation dose to the heart
Clinical Prevention for RACD
Irradiation of non-tumour tissue is unavoidable→RACD : a necessary evil ?

Cardiac dose sparing and avoidance techniques
is available nowadays.
(There are multiple techniques to minimize radiotherapy dose to the heart)
Radiation-Related Heart Disease: Up-to-Date Developments .http://dx.doi.org/10.5772/67325
Cardiac dose sparing and avoidance techniques
For curable cancers, such as breast cancer and Hodgkin lymphoma, cardiac dose protection and/or avoidance techniques might be
beneficial in minimizing RACD. For breast cancer, several techniques have been utilized clinically. These techniques include the
following: (1) radiation therapy (RT) delivery with breath control or holding techniques, (2) prone patient positioning, (3) new RT
techniques such as intensity-modulated RT (IMRT), proton therapy, or partial breast irradiation techniques, and (4) single-fraction,
intraoperative radiation.

Radiation-associated cardiac disease (RACD) —
which typically arises years or decades
after a cancer patient undergoes
radiation therapy to the chest
— should be
systematically screened for
and monitored,
with management delivered by an experienced
multidisciplinary team of cardiovascular specialists.
COMP
(Cardio-Oncology Multidisciplinary Practice)

Take Home Figures
JACC Scientific Expert Panel
( J Am Coll Cardiol 2019;74:905–27 )

Pathophysiology of RACD. Effect of XRT on various organs. (J Am Coll Cardiol 2019;74:905–27)

Imaging in RACD→ Suggested screening and diagnostic algorithm for RACD.

Pericardial
diseases
Effusion + ++++ − − + + − − −
Pericarditis ++ ++ − − + +++ − − −
Constriction + ++++ + − ++ ++++ − ++ −
Cardiac muscle
disease
Subclinical
myocardial
fibrosis
? ? − − − +++ − ? −
Nonischemic ++ ++ + + ++ ++++ ++++ ++ −
Ischemic ++++ ++++ ++++ +++ +++ ++++ ++++ ++ −
Heart failure
with preserved
ejection
fraction
++ ++++ +++ ? ++ ++ ++++ ++ −
Valvular
disease
? ++++ ++++ ? +++ +++ + ++ −
Conduction
system disease
++++ +++ ++ ? ++ ++ − − −
Coronary
artery disease
+++ +++ +++ ++++ +++ ++ ++++ ++ −
Extracardiac
vascular
disease
− − − − ++++ − − − ++++
ECG Echo
(+/− Contrast,
Strain)
Stress
Echo
Stress
Nuclear
MDCT CMR LHC RHC Extra
vascular
Ultrasound
Utility of Various Diagnostic Tests in RACD. (J Am Coll Cardiol 2019;74:905–27)

Treatment of RACD → Suggested management algorithm of patient with RACD.
(J Am Coll Cardiol
2019;74:905–27)

Ther Adv Chronic Dis
2019, Vol. 10: 1–10

The proposed mechanism of statins, colchicine, and aspirin on the reduction of
radiation-associated cardiovascular disease (RACVD). J Am Heart Assoc. 2020;9:e014668.

Radiation therapy :Existing Cardiac Imaging Recommendations Based on Prior Data
Echo
Baseline and repeated echo after radiation therapy involving the heart are
recommended for the diagnosis and follow‐up of valvular heart disease
1.Annual echocardiogram if symptomatic valvular disease
2.Screening echocardiogram 10 y after radiation therapy and every 5 y
thereafter in asymptomatic patients
ASE/EACVI (1)
Cardiac MRI
Recommended in those with suboptimal echocardiography or discrepant
results
ESC(2)
Coronary CT angiography/calcium artery calcium score
Reasonable to perform ≥5 y post radiotherapy, and further workup (eg,
coronary angiography, functional testing) is indicated for risk stratification if
there is concern for severe ischemic heart disease
SCAI(3)
SPECT ASE/EACVI(1)
1.Reasonable to screen for CAD with a functional noninvasive stress test 5–
10 y after radiation exposure in asymptomatic individuals deemed a high risk
for radiation induced heart disease
2.Repeat stress testing can be planned every 5 y if the first exam does not
show inducible ischemia
1 European Association of Cardiovascular Imaging and the American Society of Echocardiography. Eur Heart J
Cardiovasc Imaging. 2013;14:721–740.
2 European Society of Cardiology (ESC). Eur Heart J. 2016;37:2768–2801.
3 Sociedad Latino Americana de Cardiologıa Intervencionista. Catheter Cardiovasc Interv. 2016;87:895–899.

Methods for the evaluation of CVD and their applications in Cardio-Oncology
Journal of Cardiovascular Translational Research (2020) 13:417–430
Methods of cardiovascular
evaluation
Subtypes Current applications and references Path forward
Echocardiography • 2D
• 3D
• GLS imaging
• LVEF assessment via 2D echo is first line for cardiotoxicity screening [18,19,20,21,22]
• 3D TTE is superior to 2D TTE in LVEF assessment [23]
• GLS detects systolic dysfunction earlier than LVEF and has been used to identify
subclinical cardiotoxicity [21, 24,25,26]
• Standardized reporting of 3D TTE and GLS
• Assess cost-effectiveness of routine
echocardiographic monitoring
Nuclear imaging • MUGA
• SPECT
• PET
• SPECT/PET largely used for evaluation of myocardial perfusion and well suited for
patients receiving cancer therapy [27,28,29]
• PET
18
F-FDG can evaluate for inflammation, ischemia, and cellular injury following
cancer therapy [30,31,32,33,34]
• Clinical application of PET tracers as a
diagnostic method visualizes specific cellular
processes such as ROS production, apoptosis,
necrosis, cardiac remodeling, and
mitochondrial function.
• Cardiac MRI • T1 with contrast
• T2
• 4D flow MRI
• Superior LV and RV function assessment compared with echocardiography [58–59]
• LV mass and cardiomyocyte mass as additional markers of cardiotoxicity [35, 36]
• Contrast CMR for identification of myocardial fibrosis [35, 37]
• T2 imaging for presence of myocardial edema as an early sign of cardiotoxicity [61, 63–
65]
• Studies assessing the use of myocardial
fibrosis, LV mass, cardiomyocyte mass, and
myocardial edema in the diagnosis of
cardiotoxicity and guide the use of
cardioprotective therapies
• Clinical application of 4D flow MRI for
vascular evaluation
Cardiac computed tomography • Non-contrast CT
• Coronary CTA
• CAC scores from non-contrast CT for identifying coronary atherosclerosis [67, 69]
• Contrast cardiac CT for further assessment of coronary lesions [38,39,40,41]
• Valvular imaging with cardiac CT for architectural changes and pre-procedural planning
[42, 43]
• Increased use of low-dose CT for coronary
assessment
• Improved image processing of CTA for non-
invasive evaluation of stenoses
Biomarkers • Protein
biomarkers
(troponin, BNP, hs-
CRP, and others)
• Metabolomics
• Genomics
• Troponin and BNP have been most commonly used biomarkers to evaluate for
cardiotoxicity [76–93]
• IgE, hs-CRP, MMA, MPO, and others have been studied to a lesser degree
[44,45,46,47,48]
• Metabolites of cardiomyocyte energy consumption have also been identified to be
altered in animal models of cardiotoxicity [101–106]
• Various genetic variants have been associated with increased risk of cardiotoxicity
[49,50,51]
• Prospective assessment of utility of
biomarkers in risk stratification and early
diagnosis of cardiotoxicity
• Evaluate novel metabolic and genomic
biomarkers and utilize them as adjuncts to
imaging
In vitro models • Induced
pluripotent stem
cells (iPSCs)
• Stem cells obtained from human subjects can be differentiated into cardiomyocytes
and grown in culture for patient-specific testing of drug-induced toxicity and
understanding mechanisms of toxicity [111–118]
• Further development of the iPSC platform is
needed in order for cost-effective and timely
clinical testing
In vivo models •
Intraperitoneal/tail
vein injection of
chemotherapy in
rodents
• Hypertensive
animals
• Transgenic mouse
models
• Intraperitoneal injections of chemotherapy in rodents are commonly used as pre-
clinical models [52, 53]
• Transgenic mice with altered immune systems may have increased susceptibility to
chemotherapy and provide mechanistic insights [54,55,56]
• More consistent dosing protocols for
intraperitoneal injections need to be
established
• Further studies with transgenic mice will help
identify more biomarkers and drug targets.

European Society for Medical Oncology
Available online 17 January 2020
These ESMO consensus recommendations attempt to summarise best practices
for the care of cancer patients exposed to potential cardiotoxic therapy,
including chemotherapeutic agents, targeted therapies and radiotherapy (RT).

1) CAG
demonstrating
severe Cx
stenosis;
2) ‘porcelain’
ascending
aortic
calcification on
cardiac CT
3) severe mitral
annular, aorto-
mitral curtain,
and aortic valve
calcification on
cardiac CT and 4)
TTE
5) near-
transmural
inferior wall
ischemic scar
on CMR in
short-axis and
6) vertical long-
axis planes
7) complete heart
block on ECG
8) severe
pericardial
calcification on
noncontrast CT,
and 9) strain
‘bullseye’ plot
demonstrating
reduced LV AL
wall deformation
due to tethering.

Overview of cardiovascular structures being affected after radiation therapy (RT)
Tissue Involved Diagnostic Consideration Time of Presentation After RT Cardiac Evaluation
Pericardium Acute pericarditis Days to weeks TTE
Chronic effusion Weeks to months TTE
Constrictive pericarditis Years TTE, MRI, right‐sided
catheterization
Vascular tree Premature CAD Years CT, SPECT, catheterization, TTE
(stress), risk factors
MI Months to years Catheterization
Asymptomatic CAD Years CT, SPECT, catheterization, TTE
(stress), risk factors
Aortic arch calcification Years CT, MRI
Carotid stenosis Years Perfusion imaging, MRI, risk
factors
TIA/stroke Months to years Perfusion imaging, MRI, risk
factors
PVD Months to years Perfusion imaging, CT‐flow
Endocardium Valvular disease Years Echo (stress), TEE
Myocardium Myocarditis Weeks to months Echo, MRI, biomarkers
Cardiomyopathy Months to years TTE
Chronic HF Years TTE
Diastolic dysfunction Years TTE
Conduction system Heart block Months to years ECG, Holter
Clinical Cardiology. 2017;40:255–261.

Cardiac structure Incidence Time to onset after acute
radiation therapy
Myocardium 5-10% Uncertain
Pericardium 8–30%
70% (autopsy studies)
5 years
Conduction system Up to 75% 1–23 years
Vasculopathy Up to 85% 9 years
Valves Up to 81%
(Symptoms in < 30% of those
affected)
10 years (asymptomatic)
16.5 years (symptomatic)
Cardiovascular complications of radiation therapy.
Journal of Nuclear Cardiology. Sept 10, 2020

Evolution of XRT Dosage
Reduction in mean heart radiation doses for left breast cancer by
(A) year and (B) different techniques.

Cumulative incidence of
MACE stratified by
(A) pre-existing CHD (Gray’s
p < 0.001) or
mean heart dose (MHD )in
(B) patients without pre-
existing CHD (Gray’s
p = 0.025) and (C) patients
with pre-existing CHD (Gray’s
p = 0.98).

Ionizing radiation can induce both endothelial cell activation and dysfunction.
The resulting vasoconstrictive, pro-inflammatory, procoagulatory, prothrombotic, and
prohypertrophic environment can initiate and/or trigger the progression of several
pathological cardiovascular conditions, together with other vascular risk factors (e.g.,
dyslipidemia and hypertension)
Cellular and Molecular Life Sciences (2019) 76:699–728

Synthesis of the mechanisms of radiation-induced atherosclerosis
Current Atherosclerosis Reports (2019) 21: 50

A theoretical overview of how radiation-induced macrovascular and microvascular
pathologies can interact to cause myocardial ischemia, which may ultimately develop
into clinical heart disease. International Journal of Molecular Medicine Published online on: October 17, 2016

The complex etiology of vascular dysfunction
Curr Atheroscler Rep (2017) 19: 22

Radiation Therapy Delivery Techniques
RadioGraphics 2019; 39:344–366
Note.—NSCLC = non–small cell lung cancer, SABR = stereotactic ablative body radiation
therapy, 3D = three-dimensional, 2D = two-dimensional.

Generally, the probability of RACD is positively related to
the radiation dose that the heart received.
Radiation-Related Heart Disease: Up-to-Date Developments http://dx.doi.org/10.5772/67325
RACD usually occurs with a certain latency from a few hours to several decades after the heart and its substructures
receive direct or indirect irradiation.
The endpoints of RACD could be categorized as radiation-induced death from heart disease (mortality), clinical
manifestations (clinical disease), and imaging or laboratory abnormalities (subclinical disease).According the occurrence
timing of cardiac radiation response, RACD includes acute and late cardiac toxicities.

Newer technical developments in radiotherapy
Intensity-modulated radiotherapy (IMRT)
A type of 3D radiotherapy that uses computer-generated images to show the size and shape of the
tumour. Thin beams of radiation of different intensities are aimed at the tumour from many angles. This
type of radiotherapy reduces the damage to healthy tissue near the tumour.
Image-guided radiotherapy (IGRT)
A picture is composed of the tumour and surrounding anatomy using cone-beam CT scans, which are
taken while the patient is prepared to receive radiotherapy via a linear particle accelerator. This image is
fused with the original planning CT scan, and irradiation is delivered when the difference between the
two CT scans is either non-existent or is within constraints.
Dose-guided radiotherapy (DGRT)
Similar to IGRT, this technique is based on cone-beam CT images taken on the linear particle accelerator;
the radiation dose to the tumour and organs at risk is calculated and compared with the prescribed dose,
and irradiation is delivered only when the difference is either non-existent or is within constraints.
Deep inspirational breath hold (DIBH)
Patients take a deep breath during treatment and hold this breath while the radiation is delivered; the
lungs fill with air and the heart moves away from the chest. DIBH can be useful in radiotherapy of the
chest, particularly to decrease the radiation dose to the heart, as in the treatment of left-sided breast
cancer and mediastinal lymphoma.
Proton therapy
This type of radiotherapy uses protons instead of standard photons. Proton therapy may reduce the
radiation dose to healthy tissues, which may be of considerable benefit for the treatment of cancers of
the head and neck and organs such as the brain, eye, lung, spine and prostate.
MRI-linac
This instrument combines continuous MRI and the simultaneous delivery of radiotherapy. MRI is
particularly useful in some anatomical areas, such as the brain and the pelvis, owing to its high contrast
of soft tissues.

The ratio between the effects on tumour tissue versus the effects on normal tissues (also known as organs at risk) is called the therapeutic
index. The therapeutic index of radiotherapy can be defined as a sigmoidal relationship between the dose and effects on normal tissues
and tumours; the difference between both curves is used to calculate the therapeutic index (see illustration). The therapeutic index can be
increased by biological and physical methods. Biologically, by delivering low, frequent (usually daily) doses of radiation, more tumour cells
are killed than late-reacting cells such as endothelial cells and fibroblasts. Adverse effects on late-reacting tissues are usually irreversible,
which means that radiation dose must be limited to avoid such effects. The delivery of a high total radiation dose in many small ‘fractions’
thereby avoids off-target adverse effects in late-reacting healthy tissues1. The therapeutic index of radiotherapy is favourable if the
response of the tumour tissue is greater than that of the surrounding normal tissue and if severe normal-tissue complications can be
avoided. Optimized techniques physically deliver a much higher dose of radiation to the tumour than to organs at risk. Furthermore, the
use of radioprotectors and mitigators, or specific tumour radiosensitizers, may also improve the therapeutic index13,149,150,151. Currently,
tumour radiosensitization is most commonly achieved by combining radiotherapy with chemotherapeutics.
The therapeutic index of radiotherapy
NATURE REVIEWS | DISEASE PRIMERS | (2019) 5:13

Incidence of cardiovascular disease and mortality
following chest irradiation.
Front. Cardiovasc. Med., 20 March 2020

Cancer and heart failure (HF)
as comorbidity: disease
specific and shared risks.
Cancer and HF share event risk
factors associated with the
development or worsening of the
disease condition.
*Active cancer causes
inflammation, cachexia, and
anemia, which are known risk
factors for worsening HF.
*Vice versa, HF primarily promotes
chronic inflammation and
neurohormonal activation, which
also presumably contribute to
cancer progression.
* In addition, cancer and HF shares
common disease risks (green
ovals).
Circulation Journal ,Publication released
online September 12, 2020
CTRCD
(cancer therapeutics-related
cardiac dysfunction. )

Cardio-oncology, the multidisciplinary cardiovascular care of cancer patients, has been
proposed as a new approach to improve prevention, early identification and
management of cardiotoxicity. While in recent years much of the focus has been on
the early detection and prevention of heart failure, cancer therapies are associated
with a broad range of cardiovascular toxicities including cardiac arrhythmias,
hypertension and ischaemic heart disease. The present article summarises expert-
based recommendations on the management of the more prevalent non-heart failure
cancer-related cardiovascular toxicities.
Conclusions
Cardiovascular toxicity is a reality that impacts on the quality of life and overall survival
of cancer patients. Careful analysis of the needs of these patients is mandatory in order
to develop preventive strategies focused on the early detection and treatment of CV
toxicities. We need cardio-oncology multidisciplinary teams to integrate skills and
abilities and to standardise the care proces

Various approaches to study the impact of cancer therapy on the heart
Journal of Cardiovascular Translational Research (2020) 13:417–430

Radiation Associated Cardiac Disease

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