Grand Rounds Presentation 3/27/2015

CASE #1
77 YR F

SHORTNESS OF BREATH

HPI

Medical History
Atrial fibrillation
COPD

HTN
Mitral insufficiency
Obesity

Surgical History
Left rotator cuff repair
Right total knee arthroplasty

Social History
Lives with husband
Quit smoking-1ppd 50yrs

Family History
Father-CVA, CAD
Mother-CAD, Cancer

SOB for 2 weeks

Orthopnea
PND
Weakness
Lower extremity edema
Weight gain

Denies alcohol/drug use

Allergies
NKDS

T98.3 P146 R24 BP 133/86 Pulse Ox 82% on room air

141

11.1
12.19

189

34.8

Physical

3.8

105
31

13
0.7

Total bili 1.10 AST 10 ALT 26

Albumin 2.7
BNP 1056 POC trop <0.02

Examination

General Appearance: pale, alert, awake,

147

conversant, oriented
HEENT: AtNc, PERRLA, EOMI, JVD +
Cardiovascular: Irregularly irregular,
pedal edema, 3+ pitting tibial edema
Respiratory: Crackles, Oxygen-on 4L NC
GI: soft, nontender
Extremitites: moves all; pitting edema
Neuo: alert, oriented, normal speech

Alk Phos 83

ADMITTING DX

HOME MEDICATIONS

Home meds:
Metoprolol Tratrate 23mg

New onset CHF

Atrial fibrillation RVR
ED course
Cardizem 60mfg PO
ASA 325mg
Lasix 20mg IV

PO BID
Aspirine 81mg Daily
Citalopram 20mg PO daily
Tramadol 50mg Q6 prn
Rivaroxaban 20 mg c Din
Atrovastatin 10mg PO
daily
Dronedarone 400mg BID
Promethazine 25md PO
Q4 prn

ECHO

LVEF 65%, No RWMA

Left atrium moderatesevere dilation
Mitral Valve prolapse
with moderate
severe regurgitation

R/LHC

Pulmonary artery
pressure 55
Mean PCWP 27
EF 48%, 4+ mitral
regurgitation into
enlarged left atrium

CASE #2
45 YR OLD MAN

Medical History
Asthma

Surgical History
Denies

Social History
Broker
Denies alcohol, drug use
Quit smoking 5 yrs ago
20 pack yr history

PROGRESSIVE
DYSPNEA

8 months
Attributed to asthma
Not responding to
inhalers or oral steroids
Family History
Sisters died of breast cancer
Brother died of pulmonary

hypertension

Allergies
NKDA

T98.3 P100 R20

138

17
9.8

196
56

BP 121/82 Pulse Ox 80% on room air

4.2

105

35

0.7

87

Physical Examination
General Appearance: alert, awake,
oriented
HEENT: AtNc, PERRLA, EOMI, JVD +
Cardiovascular: Loud P2, S3, Grade 1,
MRLE 1+ pitting edema
Respiratory: diffuse crackles, wheezes
GI: soft, nontender
Extremitites: moves all; pitting edema
Neuo: alert, oriented, normal speech

Admitting DX
New

onset CHF
Acute Asthma
Exacerbation
ED course
Bronchodilators
Oxygen
Lasix 40mg X1

Home
Medications
Home meds:
Albuterol
Symbicort

Duonebs

ECHO

RHC

Tricuspid

PCWP

regurgitation
PAP of 75mmHg

VQ

scan pending
to rule out
embolism

Definition
Classification
Physiology &
Pathophysiology
Sings and Symptoms
Diagnostic Approach
Treatment
Prognosis
Follow up

Pulmonary Hypertension

Definition

WHO Classification of
PHTN

Factors of Late
Diagnosis
Symptoms
Pulmonary

arteries can withstand

changes in hemodynamic 10x the
normal
Delay in symptoms and signs

manifestation
With progressive decline cardiac output

Physiology Regulation of
pulmonary vascular tone
Endothelin
Prostacylcin
Nitric Oxide

Endothelin
Expressed

on endothelial and smooth muscle

cells
Endothelial cell express Endothelin-B
vasodilation
Smooth muscle cells express Endothelin-A and B
A-vasoconstriction and cellular proliferation
B-vasoconstriction

PAH

endothelin levels are elevated

Down-regulation of ETB on endothelial cells and

up-regulation on smooth muscle cells

Decrease in vasodilation, increased in vasoconstriction
Leads to constriction, proliferation and hypertrophy

Nitric Oxide
Continuously

produced in the

endothelium
Vasodilation
inhibition of platelet aggregation
inhibition of cellular proliferation
thrombus formation
inflammation

In

PAH- levels are decreased,

vasoconstriction and cellular proliferation

Prostacylcin
Produced

in the endothelial cells

Potent vasodilator

In

PAH - Reduced

Decreased vasodilation and anti-

proliferative effect

Group 1- Pathophysiology
and Pathology
Vasoconstriction

theory-

imbalance between locally produced vasodilators such

as nitric oxide and prostacyclin and vasoconstrictors

such as endothelin and thromboxane
New

data reflects the role of vascular wall

remodeling
proliferating endothelial and smooth muscle cells
abnormalities in the extracellular matrix
predisposing factors are the mutations in theBMPR2gene
that result in FPAH and some cases of sporadic IPAH
connective tissue disease, the possibility of an autoimmune
injury leading to casulopahty

Group 1- Pathophysiology
and Pathology
Destructive

vascular changes

Inflammation
vasoconstriction
Cell proliferation/hypertrophy
Tunica intima proliferation
Fibrotic changes of tunica intima- concentric and
eccentric
Tunica media hypertrophy
Tunica adventitial thickening
Thrombotic lesions
Plexiform lesions

Group 2- Pathophysiology
and Pathology
Group

2: Left heart disease

Enlarged and thickened pulmonary veins

Pulmonary capillary dilation
Interstitial edema
Alveolar hemorrhage
Distal pulmonary arteries may be

affected by medical hypertrophy and

intimal fibrosis

Group 3- Pathophysiology
and Pathology
Group

3 : Lung disease/Hypoxia

Medial hypertrophy and intimal

obstructive proliferation of the distal

pulmonary arteries
Various degree of destruction of the
vascular bed in emphysematous or
fibrotic areas

Group 4 &5- Pathophysiology

and Pathology
Group

4: Chronic thromboembolic
pulmonary hypertension
Organized thrombi attached to pulmonary

arterial medial layer in the elastic pulmonary

arteries replacing the normal intima
Complete occlusion of the lumen , or form
different grade of stenosis , webs or bands
Group

Unclear/multifactorial
Heterogeneous conditions with different

pathological pictures

Presentation
SYMPTOMS

Non-specific
Early symptom s
Dyspnea
Fatigue
Weakness
Late Symptoms

Angina
LE edema
Abdominal fullness/pain
Syncope
Dyspnea at rest

SIGNS
Accentuated P2
Pansystolic murmur of
TR
Diastolic murmur of
PR
RV third heart sound
Jugular vein
distention
Hepatomegaly
Peripheral edema
Ascites
Cool extremities

Diagnostic Approach
Unexplained

dyspnea
Comorbidity/ high risk patients
Family history of PAH
Connective tissue disease
HIV
Congenital heart disease
Chronic liver disease

Diagnostic Approach
Identifying

the presence of PHT

Identifying the cause on the bases of
clinical classification
Screening/diagnostic tools
Chest radiography
Transthoracic Doppler echocardiography
Ventilation and perfusion lung scan
Chest high resolution computed tomography
Pulmonary angiography

Diagnostic Tools
CHEST RADIOGRAPHY

Central pulmonary arterial

dilation with attenuation of
peripheral pulmonary
vasculature
Cardiomegaly , right
ventricular enlargement
Help identify underlying
pulmonary parenchymal
disease ILD, COPD,
pulmonary vascular
congestion due to left hear
disease, pleural effusion

Diagnostic Tools
Electrocardiogra
Low specificity & sensitivity
m
Provides supportive evidence
RVH, strain, right atrial dilation, left
atrial dilation

Diagnostic Tools
TEE

Initial non-invasive test

help screen/suggest
diagnosis of PH
Identify valvular
abnormalities , left atrial
enlargement, myocardial
abnormalities, pericardial
effusion, ventricular
enlargement, pressure
Congenital heart disease

Diagnostic Tools
VENTILATION AND
PERFUSION LUNG SCAN

Distinguish CTEPH
Multiple large
segmental perfusion
defects
Normal VQ rules out
Severity

Diagnostic Tools
Pulmonary
Function Test
Blood test

Uric acid, brain

natriuretic peptide,
anticentromere
antibodies, serum
creatinine, thyroid
function,
antinuclrear
antibodies, etc.

Accurate
Diagnosis

Heart failure

Determines
treatment course
Group 2-5

Treat underlying

disorder

Lung disease

Chronic PE

Group 1 PAH

Vasoreactivity
with RHC

RHC
Required to confirm diagnosis
Assess the severity of the hemodynamic

impairment

Assess vasoreactivity of the

pulmonary circulation
Short acting drugs

Inhaled NO, IV epoprostenol, IV

adenosine

Benefit from long-term therapy with

CCB
Positive acute response is mPAP
>10mmHG to reach an absolute
value of MPAP <40mmHg with
concurrent increased or unchanged
CO
Can be treated safely with high dose
CCBs

Only positive reactive

95% five-year survival

Treatment in PAH
Based

on vasoreactivity and
functional class
New York Heart Association Functional

Class
Class I: No symptoms with ADL
Class II: some symptoms with ADL, slight
limitation
Class III: symptoms with less than normal
ADL, increased limitation of physical activity
Class IV: symptoms with any activity, even at
rest

No Treatment
Untreated

= 6months
Median survival rate is 2.8 yrs
WHO FC IV 6 months
WHO FC III 2.5 yrs
WHO FC I and II 6 yrs
Scleroderma ~1yr

Prognostic Factors

Prognosis

Therapeutic Approaches
No

cure
Goal
Symptomatic relief
Quality of improvement
Survival prolongation

Basic/ Supporitve
Therapy PAH
Activity as tolerated, limit
Oxygen sat >90%,
decrease hypoxic
vasoconstrictionnocturnal desaturation
Diuretics
AC IPAH INR 2.0 2.5
(decrease in situ
thrombosis)
Digoxin
Avoid pregnancy
Immunization influenza
and pneumococcal

PAH specific therapy

Medical
Surgical therapy

Atrial septostomy

decrease right sided

pressure, improve
left sided filling
pressure
Transplant

Calcium channel blockers

Endothelial Receptor
Antagonists

Bodentan, Sitaxsentan,

Ambirisentan

Phosphodiestaerases
Inhibitors
Sildeneafil, Tadalafil,

Varadenafil

Prostaglandins
Epoprostenol, Treprostinil,

lloprost

Guanylate cyclase
stimulant -Riociguat

Treatment of PAH
CCB
Pt who show response to acute vasodilator testing

at the time of RHC

Nifedipine, diltiazem, amlodipine
Choice depends on pts baseline hear rate
Relative bradycardic nifedipine and amlodipine
Tachycardia diltiazem
120-240mg nifedipine
240-720mg diltiazem
20mg amlodipine
Limiting factors hypotension, LE edmea
Follow up 3-4 month RHC, change in functional class
Negative vasoreactivity should not be started on CCB-severe
side effects hypotension, syncope, RV failure

Prostanoids
Prostacyclin
Developed by endothelial cells
Induce potent vasodilation of all vascular beds
Inhibitor of platelet aggregation, antiproliferative
Synthesis of stable form
Epoprostenol- an infusion pump and permanent
tunnelled catheter
Lloprost- IV, oral and aerosol administration
Treprostinil- IV, SC

 Epoprostenol
Synthetic prostacyclin
Half life of 3-5minutes, stable at room temperature for

~8hrs
Administrated an infusion pump and permanent tunnelled
catheter
Start at a dose 2-4ng/kg/min and increase at a rate limited
by side effects flushing, headache, diarrhea, leg pain
Efficacy on three unblinded RCTS in patients with IPAH and
in those with PAH associated with scleroderam
Have shows that it improves symptoms, exercise capacity, and
hemodynamics
Only treatment shown to improve survival in IPAH

Endothelin Receptor
Antagonists
Endothelin-1

has vasoconstrictive
and mitogenic effects pulmonary
vascular smooth muscles-endothelinA and B receptors

Bosertan- Oral
Sitaxentan
Ambrisentan

 Bosertan
Oral
Dual endothelin-A and B receptor antagonist
Started at dose of 62.5 mg BID and uptitrated to 125mg BID after

4 weeks
Five RCTs Pilot, BREATHE-1, 2, 5 and EARLY
Showed improvement in exercise capacity, functional class,
hemodynamics, echocardiographic
Two RCT enrolled exclusively patients with WHO-FC II or patients
with Eisenmengers syndrome
Regulatory authority approval for its use in AHO- FC II and congenital
systemic to-pulmonary shunts and Eisenmengers syndrome

Side effects increase in hepatic aminotransferases 10% , dose

dependent
Liver function test monthly

Phosphodiestrease Inhibitors

Vasodilation

and antiproliferative

effects
Sildenafil- Oral
Tadalafil
Vardenafil

 Sildenafil
Oral
Selective inhibitor
RCT SUPER-1
278 PAH patients treated with sildenafil 20,
40, 80mg tid
Favorable results on exercise capacity,
symptoms
Side effects headache, flushing, epistaxis

Combination Therapy
Fail monotherapy

Some Hemodynamics, exercise

capacity and functional class improved

Follow up

Follow up