Acute Right Ventricular Failure.

Chronic Pulmonary Hypertension

and right heart catheterization.

Stefano Ghio
Divisione di Cardiologia
Fondazione IRCCS Policlinico San Matteo
Pavia
Acute Right Ventricular Failure.

Stefano Ghio
Divisione di Cardiologia
Fondazione IRCCS Policlinico San Matteo
Pavia
Acute RV failure :

• Isolated :
- Acute pulmonary embolism
- Acute RV infarction
- Rapid progression of “pre-existing PH”

• Associated :
- ADHF due to LV failure coexisting with RV
failure (and usually PH).
following the acute episode
<RV overload>
<RV overload>
<RV overload>
Transtricuspid pressure gradient
<mobile thrombi in the right heart chamber>
<mobile thrombi at TEE>
- Diagnosis and Risk Stratification of PE are strictly
linked, since:

therapy of PE depends on its severity.

Blood pressure!!!

Echo, CT

hsTnI

BNP,…
Normal TAPSE = 23 mm Reduced TAPSE = 9 mm
TAPSE is an independent predictor of prognosis in
advanced HF pts (in addition to NYHA, LVEF & DT)
Ghio et al, Am J Cardiol 2000

End point: death or

141 pts, DCM/IHD, EF<35% urgent transplantation
40
1.00

T
A 30 TAPSE>14mm
0.75
P
TAPSE

S
20
E 0.50

10 r=0.63 0.25
TAPSE<=14mm
RVEF
0 0.00
p<0.01
0 20 40 60 0 20 40 60
RVEF months
 Int J Cardiol. 2010;140(3):272-8

59 IPAH pts; median f-up 52 months

cont.
657 consecutive patients hospitalized
with a diagnosis of PE based on multi-
detector row CT scan.

The addition of RVD-CT (RV/LV d >1)

to PESI, NT-proBNP, TNI or their
combinations enhanced the likelihood
of an adverse outcome
Chronic Pulmonary Hypertension
and right heart catheterization

Stefano Ghio
Divisione di Cardiologia
Fondazione IRCCS Policlinico San Matteo
Pavia
NORMAL PRESSURES IN THE PULMONARY CIRCULATION

capillaries Veins
Small art.

PULM ART LEFT ATRIUM

PAP: PAWP: Left Atrium

Systolic: 30 mmHg Up to 15 mmHg 0 in early
Mean: 20 mmHg diastole
Diastolic 12 mmHg <18 mmHg in
end-diastole
Transpulmonary Gradient (PAPm – PAWP) <12 mmHg
 PRE-CAPILLARY PULMONARY HYPERTENSION

capillaries Veins
Small art.

PULM ART LEFT ATRIUM

PAP: PAWP: Left Atrium

Mean: >=25 mmHg Below 15 mmHg 0 in early
diastole
<18 mmHg in
end-diastole

In pre-capillary PH mPAP is above 25 mmHg

PAWP and diastolic Left heart pressures are normal
 POST-CAPILLARY PULMONARY HYPERTENSION

capillaries Veins
Small art.

PULM ART LEFT ATRIUM

PAP: PAWP: Left Atrium

Mean: >=25 mmHg Above 15 mmHg >18 mmHg in
end-diastole

In post-capillary PH mPAP is above 25 mmHg

PAWP and diastolic left heart pressures are elevated
From Pulmonary Embolism to Pulmonary Hypertension
 Pulmonary Embolism

COMPLETE RESOLUTION:
infrequent
INCOMPLETE RESOLUTION:
in the majority of cases
PROGRESSION:
to Chronic Thromboembolic Pulmonary
Hypertension (CTEPH) in “few patients” ?? %

Fedullo et al. Eur Resp J, 2000

Group 1 223 pts with PE, no history of VTE

Group 2 58 PE pts with previous DVT

24 PE pts with previous PE
 INCIDENCE of CTEPH at 2 years

Group 1 3,8%

18 pts
5.2 % if previous DVT

Group 2
33 % if previous PE
PEA: 8
«The survival rate at five years was 30% among patients
with a mean PAP that exceeded 40 mmHg at the time of
diagnosis and only 10% among those with a value that
exceeded 50 mmHg»

Int J of Cardiol 2011;154:S54-60

Poor prognosis early diagnosis (how?)
 FOLLOW-UP after PE: unknown

Scarce interest on the chronic phase after acute PE.

How to follow-up pts surviving acute PE?

Chest X ray
blood gas analysis
Compression venous ultrasonography
Echocardiography
Lung scintigraphy
Computed tomographic pulmonary
angiography
D-dimer testing
78 pts who underwent acute PE;
Repeated echo during 1° year; clinical f-up up to 5 years
PAPs > 50 mm Hg at echo in acute phase
Age> 70 yrs

High Risk 5 yr prognosis:

of developing CTEPH at 1 year Cancer, age,
PAPs >30 mmHg
CTEPH incidence: 5% at 30 days
PAPs remains stable after 38 days

38° giorno
Mechanisms of CTEPH
are partly unknown CTEPH

“the search for the

missing link”

Acute PE

Incidence PE: 1 per 1.000 inhabitants/year

Incidence CTEPH: 1 per 1.000.000 inhabitants/year
CTEPH is only one of several forms of
Chronic Pulmonary Hypertension.

It is surgically treatable
(pulmonary endarterectomy - PEA).
 PULMONARY ENDARTERECTOMY: THE PAVIA EXPERIENCE
MAIN WORLD CENTERS for PEA

Cambridge, UK
≈100 PEAs / year
NATIONAL REFERRAL PROGRAM BY LAW

Pavia, Italy
≈80 PEAs / year

San Diego, California, USA

≈120 PEAs / year
NATIONAL REFERRAL PROGRAM
FOR EXCELLENCE Paris, France
≈100 PEAs / year
NATIONAL REFERRAL PROGRAM
FOR EXCELLENCE

Courtesy: A.D’Armini
 Chronic Thromboembolic
Pulmonary Hypertension

is just one of the many diseases which

may be associated with this hemodynamic
condition (PH)
 2015

Definition based on hemodynamic evaluation

(echo allows estimate of sPAP, not of mPAP)
 Clinical Classification
of Pulmonary Hypertension.
 Classification of PH

(>30 diseases are included in this classification)

This classification is simple and useful to understand

- what is PH (hemodynamic condition),

- what is PAH (a group of diseases characterized by PH),
- and how to make diagnosis of PAH (by exclusion).
 Classification of PH

Pneumologist/radiologist

Nuclear medicine specialist

cardiologist
The classification is useful to understand:
which pts have to be treated with generic therapy
which patients may benefit from specific PAH drugs and
which patients needs surgery.
Classification of PH
The classification is useful to understand the pathogenesis
of PH.
Classification of PH
Istopathologic lesions of pulmonary arterioles in
group 1 PH (PAH).
Normal PAH

Plexiphorm
lesions

Intimal Adventitial
proliferation Medial Fibrosis
hypertrophy
Endothelial dysfunction in IPAH

Vascular
Smooth muscle cells

Phosphodiesterase type
5

Adapted from Humbert M N Engl J Med 2004; 351: 1425

Prostacyclin synthase expression is decreased in lungs
from patients with severe PH

Decreased immunostaining for prostacyclin synthase in small size pulmonary

arteries of PAH patients

Tuder AJRCCM 1999;159:1925

Enhanced Thromboxane and Depressed Prostacyclin Levels in Pulmonary
Hypertension

↑ Thromboxane A2 ↓ Prostacyclin
11-Dehydro-thromboxane B2 2,3-Dinor-6-keto-PGF1
(pg/mg of creatinine) (pg/mg of creatinine)
800
10,000

8000 600

6000
400
4000
200
2000

0 0
Normal Primary PH due Normal Primary PH due
controls PH to other controls PH to other
causes causes

Christman et al. N Engl J Med. 1992;327:70

 eNOS expression is reduced in the lungs of patients
with pulmonary hypertension

Decreased immunostaining for eNOS in small size pulmonary arteries of PAH

patients

Giaid and Saleh. N Engl J Med 1995; 333:214

 PDE5 upregulation in PAH pts
Wharton J, AJRCCM 2005; 172:105

<< strong upregulation of the PDE5 in human

pulmonary artery muscle cells.
The antiproliferative effects of this signaling pathway
with PDE5 inhibitors such as sildenafil may be
significant in the chronic treatment of PH>>
 The discovery of endothelin

A novel potent vasoconstrictor peptide produced by

vascular endothelial cells
Masashi Yanagisawa, Hiroki Kurihara Sadao Kimura, Yoko Tomobe, Mieko Kobayashi,
Youji Mitsui, Yoshio Yazaki, Katsutoshi Goto & Tomoh Masaki

A 21-amino acid peptide purified from endothelial cells

Demonstrated to possess potent vasoconstrictor properties

Adapted from Yanagisawa M, et al. Nature. 1988;332:411.

Expression of ET-1 in the lungs of PAH patients

iPAH
Normal Small size PA Plexiform lesion

Increased immunostaining for ET-1 in small size

pulmonary arteries of PAH patients

Giaid N Engl J Med 1993; 328:1732-9.

 Endothelin plasma levels are increased in PAH

Idiopathic PAH1 Scleroderma2 Congenital

heart disease3
p < 0.001 p < 0.05 p < 0.001
10 10 5

 ET-LI (PV-RV)
8 4
of ET-1(pg/ml)
Concentration

8
IrET-1 (pg/ml)

6 3

(pg/ml)
4 2
6
2 1
0 4 0
Non- IPAH Non- PAH Non-PH PH
IPAH PAH

1StewartDJ Ann Inter Med 1991; 114:464-9.

2Vancheeswaran R J Rheum 1994; 21:1838-44.
3Yoshibayashi M Circulation 1991; 84:2280-5.
 2015 Classification of PH
This classification is not complex, it is simple. The
complexity derives form the fact that it is a
SIMPLIFICATION of the real world and in the real
world you may find pts in whom etiology of PH is
multifactorial (i.e. cannot be defined by a single group).

• CHD pts with previous pulm. embolism (class 1 + 4).

• Pts with parenchimal lung disease with “out of
proportion” PH” (?) (class 3 + 1).
• Pts with LV dysfunction and reactive PH (classe 2 + 1).
•…
Classification of Pulmonary Hypertension.

What is the necessary clinical consequence,

having said that PH is a condition which can be
found in more than 30 different diseases?

A precise diagnosis must be to obtained in each

patient.
Different disease may require different
treatments.
 2015
- The PH
diagnostic flow
chart is complex
and requires
several
examinations
performed by
different
specialists.
- Diagnosis
should be
performed in an
expert referral
center.
 Diagnosis of Pulmonary Hypertension.
DD Specific Diagnosis Further Measures, if necessary
Familial Form • Detailed Family History • Stress Echo and cardiac catheterization of First Degree
Relatives
Autoimmune Disease • Antinuclear Antibodies • Platelet Antibodies
• Extractable Nuclear Antigens • Barium Swallow Test/Microangioscopy/Schirmer’s Test
• Thyroid Function and Thyroid Antibodies • Skin Biopsy
• Urine Analysis
Chronic Viral Infection • HIV Test • Liver Biopsy
•Cytomegalus virus (CMV)
•Hepatitis B + C
Left-to-Right Shunt • Doppler Echocardiography • Transoesophageal Echocardiography
• Angiography
Liver Disease • Blood Chemistry • Liver Biopsy
• Epigastric Sonotopography
• Oesophageal Gastroscopy
Pulmonary Disease • Pulmonary Function Test • BAL
• Blood Gas Analysis • Lung Biopsy
• CO Diffusion
• High Resolution CT
Pulmonary Venous • Echocardiography • Exercise Testing (Catheter/RNV)
Hypertension • High resolution CT • Coronary Angio
• LV Angio
• Lung Biopsy
Pulmonary Embolism • Perfusion Scintiscanning + Ventilation • High resolution CT
Scintiscanning • Deep Vein Diagnostics
• Spiral-CT or Pulmonary Artery Angiography • Thrombophilia Diagnostics
Other Disease • Differential Blood Count • Specific Tests
• BAL • Histology
 PAVIA multidisciplinary team for PH patients

• Cardiologia S Ghio, L Scelsi, C Raineri, A Turco

• Reumatologia R Caporali, L Cavagna, V Codullo

• Pneumologia F Meloni, T Oggionni, A Corsico

• Infettivologia A Di Matteo

• Radiologia R Dore

• Medicina Nucleare C Aprile

• Cardiochirurgia AM D’Armini, M Morsolini

• Ematologia, Epatologia, Otorino …

 The diagnostic flow chart of PH

We need a “dedicated” cardiologist to “supervise”

the diagnostic examinations flow chart.
“Dedicated” since echo and right heart cath have to
be performed in a specific way in PH patients if we
want to obtain all the necessary information from
such examinations.
PAH (i.e. group 1 PH) is a rare disease

carries poor prognosis,

difficult to diagnose
therapy extremely expensive (up to 15000 euro/m)
ultimately needing lung transplant
to be treated in specialized centers.
Epidemiology of PAH

(in France and in England)

PULMONARY ARTERIAL HYPERTENSION IN FRANCE:

Results from a National Registry

All consecutive adult ( 18 yr)
October 2002- October 2003

N. pts 674 pts

Mean age 50+/-15 yr (range 18-85 yr)

Incidence 2.4 case/million/year

Prevalence 15 cases/million

Humbert M et al. Am J Respir Crit Care Med 2006;173:1023-1030

 Epidemiology of PAH.
Group 1 (PAH) represents about 3.5% of all forms of PH
1.1 Idiopatic pulmonary arterial hypertension
In the French Registry 40% of patients were IPAH

1.2 Heritable pulmonary arterial hypertension

In the French Registry 4% of patients were
heritable/familiar PAH
1.3 Drugs/toxins induced pulmonary arterial
hypertension
In the French Registry 10% of patients PAH induced by
drugs or toxins.
1.4 Associated pulmonary arterial hypertension
In the French Registry 15% of PAH patients were
associated with connective tissue disease (mainly
systemic sclerosis); 10% were associated with portal
hypertension; 6% were associated with HIV; 11% of
patients were Eisenmenger.
Prognosis
of PAH.
 PROGNOSIS of PAH

An American Registry supported by the National

Institute of Health (NIH) (1981-1985) (NO THERAPY)

Median survival:
2.8 YEARS FROM DIAGNOSIS

At 1 year survival = 68%

At 3 years survival = 48%
At 5 years survival = 34%

D’Alonzo GE et al. Ann Intern Med 1991;155:343-349

 Prognosis of PAH

survival: 1 yr: 82.9; 2yrs: 67.1; 3 yrs: 58.2%

Prognosis: what IS IMPORTANT?

• NIH registry: Ann Intern Med 1991; 115:343

• J Sandoval et al: Circulation 1994; 89:1733

P(t) = H(t)A
H(t) = 0.88-0.14t+0.01t2
A = e(0.007325x)+(0.0526y)-(0.3275z)
(x=PAPm, y=RAP, z=CI)

“Mortality in PPH is largely associated

with hemodynamic variables that assess
right ventricular function”
59 IPAH pts; median f-up 52 months
3 echo indicators of RV function: TAPSE, Degree of TR, LV EI-d

EId=2
Clinical and Prognostic Relevance of the Echocardiographic Evaluation of Right
Ventricular Geometry in Patients with Idiopathic Pulmonary Arterial
Hypertension.
S.Ghio et al.
American Journal of Cardiology 2010, accepted for publication

RV dilatation is a negative prognostic factor.

RV hypertrophy might be protective.
Treatment
of PAH.
Pathogenetic therapy in IPAH pts

Vascular
Smooth muscle cells
NO
PGI2
ERA
Phosphodiesterase type
5

PDE5-i Adapted from Humbert M N Engl J Med 2004; 351: 1425

drug Costs for 1 month of therapy
(average, in euros)
PDE5-i 600

ERA 2400

Prostanoid (inhaled) 2600

Prostanoid (parenteral) Up to 10-15000

185 pts with IPAH or PAH associated with CTD, HIV, CHD randomised to bosentan or
placebo. Follow-up 6 months.
End-points: 6MWT, RH hemodynamics, TTCW

P<0.0001

Relative risk reduction = 47%

p=0.0114
 Conclusions:
• EARLY trial demonstrates that mildly symptomatic PAH
patients present a progressive hemodynamic
and clinical deterioration if left untreated, despite the
maintenance of exercise capacity.
 How is it possible early diagnosis of PAH?
screening of pts at risk

• pts with connective tissue disease (mainly systemic

sclerosis)
• pts with HIV infection
• pts with portal hypertension
 How is it possible early diagnosis?
screening of pts at risk

Which technique for screening?

The ideal technique is: Biomarker?
• Simple
• Inexpensive
• Easy to perform
• High sensitivity
• High specificity
N-t proBNP measured in 17 HIV/PH pts and in 77 HIV pts.
Median (IQR values) 1412 (574-2236) in PH+ pts and 29
(7-48) in PH- pts.
Normal N-t proBNP values were observed in 3 PH+ pts, all
having normal right ventricles at echo examination.
Conclusion: good specificity but poor sensitivity of BNP
sampling.
135 patients (96 limited, 39 diffuse SSc); PAH was found in 20 patients. BNP
value of 64 pg/ml had a sensitivity 60% and a specificity of 87% to identify
PAH.

Conclusion: good specificity but poor sensitivity of BNP sampling.

 Screening means echocardiography

The ideal technique is: Echocardiography is:

• Simple • Simple
• Inexpensive • Inexpensive
• Easy to perform • Easy to perform
• High sensitivity • Moderate sensitivity
• High specificity • Moderate specificity

Which means that dedicated echocardiographists are necessary

 2015
- RHC is a key
examination in
the PH diagnostic
flow chart.
Right
giugular
vein
Right
giugular
vein