Download Carcinoid Heart Disease (CHD)

NET MASTERCLASS
What’s new in 2015: an interactive workshop
Carcinoid Heart Disease (CHD)
Dr. Christos Toumpanakis MD PhD FRCP
Consultant in Gastroenterology/Neuroendocrine Tumours
Hon. Senior Lecturer University College of London
Neuroendocrine Tumour Unit - ENETS Centre of Excellence
ROYAL FREE HOSPITAL, London,UK
Carcinoid Syndrome
MIDGUT NETs, OVARIAN NETs, BRONCHIAL NETs
Flushing, diarrhoea,
bronchospasm, Carcinoid Heart Disease
•
•
30 – 40 % of patients with liver metastases
5% of patients with carcinoid syndrome do not have liver metastases
“Carcinoid crisis”
Severe symptoms of carcinoid syndrome + hypotension during
procedures that involve GA, as well as in TAE, and when the
patient is on inotropes
Carcinoid Heart Disease
•
May develop in 30-50% of patients,
with carcinoid syndrome (midgut
NETs with hepatic or retroperitoneal metastases, ovarian
NETs and bronchial NETs).
•
It represents the development of
fibrotic plaques on the heart valves.
•
It DOES NOT mean development of
myocardial metastases.
•
Its development is associated with
30 – 50% reduction in the expected
survival of those patients.
Battacharyya S , Toumpanakis C et al, AJC 2008
How CHD develops?
•
It is mediated by vasoactive substances secreted by the NETs
cells:
– 5 hydroxytryptamine
Deposition of Endocardial
(5-HT, serotonin)
Plaques Composed of:
• Myofibroblasts
– Prostaglandins
• Smooth muscle cells
– Histamine
• Deposits of ECM (including collagen &
myxoid ground substance)
– Bradykinin
– Substances with fibroblast
proliferative properties
• Tachykinins: substance P, neurokinin A, neuropeptide K
• Transforming growth factor β
Fox DJ & Khattar RS. Heart 2004;90:1224-8.
Bernheim AM et al, Progress in Cardiovascular Diseases, 2007; 49(6): 439-451.
The Pathways Responsible for the Development
of CHD
Are still uncertain.
The disease is likely to be multifactorial.
SEROTONIN
5HT2B
is a major player and is considered to be a major initiator of the
fibrotic process, by targeting the 5-HT2B receptor.
R. Dobson et al., International Journal of Cardiology 2014; 173: 29-32.
Gustafsson BI et al, International Journal of Cardiology 2008; 129: 318-324.
Endocardial deposits of
fibrous tissue
• occur primarily on the downstream side of the valve leaflets (on the
ventricular aspect of the tricuspid valve and the pulmonary arterial side of
the pulmonary valve) - preferentially right-sided lesions.
– the lungs filter the vasoactive peptides, inactivating them in the
pulmonary circulation before they reach the left atrium
Left-sided valvular pathology (5-10%) - seen only in patients with bronchial
carcinoid or patent foramen ovale or in those with poorly controlled, severe
carcinoid syndrome that overwhelms the pulmonary degradative capacity.
Palaniswamy C et al., Cardiol Rev 2012;20:167-76.
Gustafsson BI et al., Int J Cardiol 2008;129(3):318-24.
• “Carcinoid Plaque” - composed of smooth muscle cells &
myofibroblasts forming a white fibrous layer lining on the
endocardial surface of cardiac valves, superficial to normal
valve.
Bhattacharyya S et al. Circ Cardiovasc Imaging. 2010;3:103-111.
• The disease is characterized by retraction & fixation of
predominantly the right-sided valve leaflets, leading to a
combination of valvular regurgitation & stenosis, which
ultimately can progress to right heart failure.
A. Dilated right heart, with thickened, retracted tricuspid valve leaflets
B. Colour flow Doppler revealing severe jet of TR filling a dilated right
atrium.
C. Continuous wave Doppler showing dense jet of TR.
Bernheim AM et al., Prog Cardiovasc Dis 2007;49(6):439-51.
Clinical Features of CHD
• Asymptomatic period - variable
• Dyspnea, fatigue
• Ascites and peripheral edema
- Cardiac
- Hepatic
- Nutritional
- Combination
NET Biomarkers for screening / diagnosis
No CHD
A)
24h urine 5-HIAA levels
Significantly higher in patients
with CHD. Patients with CHD have
on average, 2 to 4-fold higher
values of serum serotonin, and
platelets serotonin.
Low specificity.
B)
Chromogranin-A (CgA)
Sensitivity of CgA to predict
severe CHD was 100%, but
specificity was only 30%.
A level of 784mcg/L resulted in
specificity of 75% and sensitivity
of 73%.
CHD
5-HIAA
Lundin et al, Circulation 1988
Zuetenhorst et al, Cancer, 2003
Korse et al, J Clin Oncol 2009
NET biomarkers for prediction
of development and / or progression of CHD
23 patients, 8 had / developed CHD
71 patients
• Development and progression of CHD were linked to 5-HIAA levels.
• 5-HIAA > 300 μmol/L is independent predictor for development and
progression of CHD (2-3 fold increase in risk). Multivariate model, in a
prospective study of 252 patients.
• No significant value was noted for Chromogranin-A.
Denney et al, J Am Coll Cardiol 1998
Moller et al, NEJM 2003
Bhattacharyya et al, Am J cardiol 2011
Natriuretic peptides
for screening / diagnosis of CHD
NT pro-BNP
CHD
200 pts were screened, NT pro-BNP
39 had CHD.
No CHD
CHD
ANP
No CHD
ANP levels were higher in CHD, but no statistically significant.
Median NT pro- BNP was significantly higher. Cut-off level : 260 pg/ml, sensitivity 92% & specificity 91%.
• Negative and positive predictive values : 0.98 & 0.71 respectively.
• Good correlation with CHD ECHO score and functional NYHA class.
Zuetenhorst et al, Br J Cancer, 2004
Bhattacharyya et al, Am J Cardiol 2008
NT pro-BNP as a predictor of survival
•
•
Worse survival in raised levels.
Patients with raised NT proBNP and CgA levels have a
16% survival probability in 5 years.
Zuetenhorst et al, Br J Cancer, 2004
Korse et al, J Clin Oncol 2009
Central role of c. ECHO for diagnosis
•
The ECHO spectrum is wide.
•
Patients with diffuse thickening of
valve leaflets or isolated thickening of
a single valve leaflet without
significant reduction in leaflet
mobility or the development of
valvular regurgitation may represent
the early stages of carcinoid heart
disease.
•
Advanced techniques such as 3D TTE
or 3D TEE are helpful in identifying
and assessing valve pathology,
particularly in the pulmonary and
tricuspid valves, because all leaflets
may not be visualized on 2D
echocardiography.
S. Bhattacharyya et al. Circ Cardiovasc Imaging. 2010
Complementary role of cardiac MRI
•
CMR can be a valuable adjunct
where echocardiographic windows
are poor or structures such as the
pulmonary valve are difficult to
visualize.
•
Morphological features of severe
carcinoid heart disease can be
delineated with assessment of
valvular regurgitation, stenosis, and
quantification of ventricular volumes.
•
CMR enables measurement of size of
metastases and is able to offer
information regarding extension into
extracardiac structures, which is not
available on echocardiographic
techniques.
S. Bhattacharyya et al. Circ Cardiovasc Imaging. 2010
Complementary role of CT
- Assessment
of cardiac valves and RV function
- Pre-surgical assessment of coronary arteries
- Assessment of myocardial metastases and their
relationship with affected cardiac valves
O.Lazoura presentation, 1st International CHD Symposium, London, 09/2014
Medical Management of CHD
• Watchful waiting for symptoms
• Diuretics for edema – loop or thiazide
- May reduce cardiac output
- Fatigue may worsen
• Limited alternative medical options
- Digoxin or ACE
Bernheim AM, Connolly HM, Pellikka PA.
Curr Treat Options Cardiovasc Med. 2007
Surgical management of severe CHD
Indications: Individualized
– Symptomatic right heart failure
– Fatigue, dyspnoea  oedema, ascites
– Progressive RV enlargement /
dysfunction
– Prior to hepatic surgery
Will valve surgery with inherent risks (mortality 10-25%) result
in symptomatic improvement and survival benefit?
Askew JW, Connolly HM.
Curr Treat Options Cardiovasc Med. 2013
Functional Improvement following
valve surgery for CHD
Significant functional improvement after surgery.
Erasmus University Medical Centre, Rotterdam, The Netherlands EJCTS 2012
Survival of Patients with Symptomatic
Carcinoid Heart Disease
100
Surgical Rx compared with
historical medical controls
80
Survival
(%)
60
40
26 Surgical Pt
20
40 Medical Pt
0
0
1
2
3
4
5
Years
Connolly et al; JACC 1995
Timing of Operation
Prosthesis
& Surgical
Risks
Progressive
Debility
SURGICAL MANAGEMENT of CHD
Choice of Valve Prosthesis
• More controversial.
• No large series have compared the choice of valve prosthesis.
• Biological valves are usually preferred because:
- They have an acceptable lifespan.
- Somatostatin analogues and other antitumour therapies may theoretically
protect the valve from deposition of further carcinoid plaques.
- They do not require anticoagulation and consequently lower the risk of
bleeding in patients with hepatic dysfunction and also reduce the risk of
valve thrombosis (mechanical valve thrombosis is 4% per year).
Raja SG et al, Future Cardiol. 2010
Non – surgical, interventional options
• Percutaneous catheter-based interventions clearly improve the
therapeutic options in CHD by minimizing invasiveness, avoiding general
anesthesia and allowing staged procedures.
• Feasible mainly for aortic valve, potentially for pulmonary valve and
closure of PFO.
• Not suitable for mitral valve.
• Not suitable for tricuspid valve. However, heterotopic single or dual caval
valve implantation, for severe TR seems feasible and safe..
Carcinoid syndrome
Resistant to SSTA
Exclude
other
causes
Radiological
progression
No radiological
progression
• Optimize SSTs
• Add interferon
• Clinical trials (Telotristat
Etiprate)
• Debulking surgery
•
PRRT
• ? Everolimus
Predominantly
Liver disease
TAE
RFA
? SIRT
Take Home Messages
• CHD may develop in 30-50% of patients, with carcinoid syndrome and its
development may decrease survival.
•
Aggressive carcinoid syndrome treatment may prevent the development
and progression of CHD.
• NT pro-BNP seems to be a good screening biomarker.
• Cardiac ECHO remains the diagnostic modality of choice.
• Limited medical therapeutic options.
• It is important to identify the “right” time for valve replacement.
• Advances in surgical treatment improved survival.
• Percutaneous catheter-based interventions seem to be promising
alternatives in poor surgical candidates.
• Experienced multidisciplinary team required for state-of-the-art
management.
1st International Symposium for
Carcinoid Heart Disease – London 4/9/2014
• 89 delegates from
10 different countries
UK, US, Germany, France,
Sweden, Norway,
Denmark, Netherlands,
Ireland, Israel
• 36 : 40% NET physicians
• 53 : 60% Cardiologists
(Consultants, Trainees,
Technicians)
Thank you very much