DECLARATION OF CONFLICT OF INTEREST
ESC Congress 2011
Pathophysiology of HFPEF
Vascular Remodeling &
Pulmonary Hypertension
Carolyn S.P. Lam
MBBS, MRCP, MS
Case Presentation
• 81 yo woman with dyspnoea & oedema
• H/o systemic hypertension & AF
• BP 166/84, HR 74, JVD, bilat crepitations
• CXR: mild cardiomegaly, pulm congestion
• Hb, Creatinine normal; BNP 220
• Echo: LVEDVI 94, LVEF 65%, mild RV
enlargement with normal RV systolic function,
flattening of IVS, biatrial enlargement, mod
TR, mild MR, E/e’ 24, PASP 80 mmHg
Cardiac Catheterization
100
Baseline
90
80
70
60
PA 80/31, mean 49mmHg
50
40
30
20
PCWP 22 mmHg
10
RA 15 mmHg
0
CI 2.3 L/min*m2, PVR 6.4 WU
Boilson BA, Shirger JA, Borlaug BA. Eur J Heart Fail 2010
Is this…
A. Pure “diastolic” heart failure?
B. Age-related vascular remodeling and
diastolic dysfunction (DD)?
C. Heart failure with preserved ejection
fraction (HFPEF) with 2°pulmonary
hypertension?
D. Idiopathic pulmonary arterial
hypertension (IPAH) with DD from
ventricular interdependence?
Paulus W J et al. Eur Heart J 2007
Diastolic Heart Failure
HF cases:
Referred
N=47
34%F
59±12y
Controls:
Healthy
Young
Zile NEJM 2004
Diastolic Dysfunction in HFnlEF
Population-based (Olmsted County)
Lam, C. S.P. et al. Circulation 2007
LV Pressure (mmHg)
Pressure-volume loop
EDPVR
LV Volume (ml)
Pressure-volume loop
LV Pressure (mmHg)
ESPVR
Ea
EDPVR
LV Volume (ml)
LV Pressure (mmHg)
Pressure-volume loop
CON
LV Volume (ml)
LV Pressure (mmHg)
Pressure-volume loop
HFpEF
Beyond diastolic
dysfunction, systolic
vascular-ventricular
stiffening are
present in HFpEF
CON
LV Volume (ml)
Lam C et al. Circulation 2007
Impact of Vascular-LV Stiffening
Before & during
isometric
handgrip a
patient with
HFnlEF
Kawaguchi M et al. Circulation 2003
Vascular-LV Coupling
Kawaguchi, M. et al. Circulation 2003
Vascular-LV Coupling
Kawaguchi, M. et al. Circulation 2003
Age-Related
Systemic Arterial Stiffening
♀
♂
Redfield MM et al Circulation 2006
Age-Related
Systolic LV Stiffening
♀
♂
Redfield MM et al Circulation 2006
Age-Related
Diastolic Dysfunction
♀
♂
Redfield MM et al Circulation 2006
Is this…
A. Pure “diastolic” heart failure?
B. Age-related vascular remodeling
and diastolic dysfunction (DD)?
C. Heart failure with preserved ejection
fraction (HFPEF) with 2°pumonary
hypertension?
D. Idiopathic pulmonary arterial
hypertension (IPAH) with DD from
ventricular interdependence?
Age-Related Vascular Remodeling
• In the systemic circulation, age-related
vascular stiffening contributes to isolated
systolic hypertension & adverse outcome
• In the pulmonary circulation, less is known
about age-related changes in pulmonary
artery systolic pressure (PASP) and any
prognostic impact of elevated PASP in the
general community
Figure 2
Association of SBP & PASP with Age
Olmsted County General Population
SBP (mmHg)
200
Systemic circulation
Overall: r=0.40; p<0.001
Women: r=0.45; p<0.001
150
C
100
50
40
B
Men: r=0.32; p<0.001
60
80
Age (years)
100
Pulmonary circulation
Overall: r=0.31; p<0.001
60
PASP (mmHg)
A
Women: r=0.34; p<0.001
38
24
15
40
Men: r=0.26; p<0.001
60
80
100
Age (years)
Lam C et al. Circulation 2009
Figure 2
Association of SBP & PASP with Age
% Increase
1.2
1.1
PASP
SBP
1.0
0.9
45-54 55-62 63-71 72-96
Age quartiles (years)
Lam C et al. Circulation 2009
Figure 4A
Entire population
PASP & Survival in the General
Population
Cumulative Survival
Overall Log Rank p<0.001
1.00
0.95
0.90 PASP Quintile
1: 15-23 mmHg
2: 24-25 mmHg*
3: 26-29 mmHg*
4: 30-32 mmHg
5: 34-66 mmHg
0.85
0
2
4
6
Time (Years)
8
HR = 2.73 (unadjusted) or 1.46 per 10 mmHg
(adjusted for age, PP, EF, E/e’ & FEV1)
Lam C et al. Circulation 2009
Is this…
A. Pure “diastolic” heart failure?
B. Age-related vascular remodeling and
diastolic dysfunction (DD)?
C. Heart failure with preserved
ejection fraction (HFPEF) with
2°pulmonary hypertension?
D. Idiopathic pulmonary arterial
hypertension (IPAH) with DD from
ventricular interdependence?
PH & Left Heart Disease
• Left heart disease is a common cause
of secondary PH
• Severe LV systolic dysfunction
• Mitral/ aortic valve disease
• Presence of PH portends poor
prognosis in these patients
• Less is known about PH in HFPEF
Oudiz RJ Clin Chest Med 2007
Pulmonary Hypertension
Pulmonary hypertension (PH) is
highly prevalent in HFpEF
Lam C.S. et al J Am Coll Cardiol. 2009;53:1119-26
Pulmonary Hypertension
Lam C.S. et al J Am Coll Cardiol. 2009;53:1119-26
Pulmonary Hypertension
Pulmonary Venous HTN
↑ PASP
Reactive PAH
↑ PASP
Chronic PA Remodeling
↑ PASP
PH: marker of the severity & chronicity of
clinically significant pulmonary venous
congestion in HFpEF?
Diagnostic Impact of PH in HFpEF
Lam C.S. et al J Am Coll Cardiol. 2009;53:1119-26
Prognostic Impact of PH in HFpEF
Lam C.S. et al J Am Coll Cardiol. 2009;53:1119-26
Invasive Data
Dartmouth Dynamic Registry of pts with LVEDP>15 mmHg
& LVEF≥50% at cardiac cath (N=455):
PH (mPAP>25 mmHg) in 239 (52.5%)
Leung CC et al. Am J Cardiol 2010
Invasive Data
Dartmouth Dynamic Registry of pts with LVEDP>15 mmHg
& LVEF≥50% at cardiac cath (N=455):
PH (mPAP>25 mmHg) in 239 (52.5%)
Risk factors for PH in HFPEF
Leung CC et al. Am J Cardiol 2010
Is this…
A. Pure “diastolic” heart failure?
B. Age-related vascular remodeling and
diastolic dysfunction (DD)?
C. Heart failure with preserved ejection
fraction (HFPEF) with 2°pulmonary
hypertension?
D. Idiopathic pulmonary arterial
hypertension (IPAH) with DD from
ventricular interdependence?
Unexplained PH in the Elderly
Consecutive pts (N=197) from Mayo PH Clinic with
suspected IPAH undergoing RHC
≥ 65y
24%
< 65y
76%
Shapiro BP et al. Chest 2007
Unexplained PH in the Elderly
Consecutive pts (N=197) from Mayo PH Clinic with
suspected IPAH undergoing RHC
↑PCWP
in 56%
≥ 65y
24%
< 65y
76%
↑PCWP
in 19%
Elderly pts with “unexplained” PH often have
↑PCWP despite normal EF
Shapiro BP et al. Chest 2007
High (>15) versus Low PCWP
• Similar PASP
• Similar RV size
• Similar RV function
High (>15) versus Low PCWP
•
•
•
•
Similar PASP
Similar RV size
Similar RV function
↑ PCWP not attributable to ↑
ventricular interdependence
Back to the patient …
Case Presentation
• 81 yo woman with dyspnoea & oedema
• H/o systemic hypertension & AF
• BP 166/84, HR 74, JVD, bilat crepitations
• CXR: mild cardiomegaly, pulm congestion
• Hb, Creatinine normal; BNP 220
• Echo: LVEDVI 94, LVEF 65%, mild RV
enlargement with normal RV systolic function,
flattening of IVS, biatrial enlargement, mod
TR, mild MR, E/e’ 24, PASP 80 mmHg
Is this…
A. Pure “diastolic” heart failure?
B. Age-related vascular remodeling and
diastolic dysfunction (DD)?
C. Heart failure with preserved ejection
fraction (HFPEF) with 2°pulmonary
hypertension?
D. Idiopathic pulmonary arterial
hypertension (IPAH) with DD from
ventricular interdependence?
Is this…
 Diastolic heart failure
 Age-related vascular remodeling and
diastolic dysfunction (DD)
 Heart failure with preserved ejection
fraction (HFPEF) with 2°pulmonary
hypertension
× Idiopathic pulmonary arterial
hypertension (IPAH) with DD from
ventricular interdependence
Distinguishing HFPEF-PH from IPAH
Distinguishing HFPEF-PH from IPAH
PH Connection Registry at University of Chicago:
HFPEF-PH (PCWP>15 & PVR>2.5 and/or TPG>12)
versus IPAH (mPAP>25 & PCWP<15)
Thenappan T et al Circ Heart Fail 2011
Distinguishing HFPEF-PH from IPAH
Model 1 (age)
Model 2 (+ clinical RF)
Model 3 (+ echo)
Model 4 (+ cath)
Thenappan T et al Circ Heart Fail 2011
Symptoms
HF Dx unclear
Echo Doppler
EF<40% or Valve
Disease
PH + Normal EF
DHF
Likely
DHF
Uncertain
DHF
Unlikely
Exclude Other
Causes of PH
DHF
Exclude Other
Causes of PH
RHC
RHC
PCWP ≥ 15
PVR < 3
PCWP ≥ 15
PVR ≥ 3
PCWP < 15
PVR ≥ 3
PCWP<15
PVR ≥ 3
DHF
Hypertensive?
Nipride or NTG
DHF Risk
Factors
PAH
PCWP < 15
PVR ≥ 3 WU
PCWP < 15
PVR < 3 WU
Many
Few
Pre-capillary PH +
Diastolic Dysfunction
DHF
Exercise
or Volume
PAH
? Treat PH
RCT
Elevated PCWP
DHF
PCWP ≥ 15
“DHF Uncertain”
Normal PCWP
PAH
Hoeper et al JACC 2009
Symptoms
HF Dx unclear
Echo Doppler
EF<40% or Valve
Disease
PH + Normal EF
DHF
Likely
DHF
Uncertain
DHF
Unlikely
Exclude Other
Causes of PH
DHF
Exclude Other
Causes of PH
RHC
RHC
PCWP ≥ 15
PVR < 3
PCWP ≥ 15
PVR ≥ 3
PCWP < 15
PVR ≥ 3
PCWP<15
PVR ≥ 3
DHF
Hypertensive?
Nipride or NTG
DHF Risk
Factors
PAH
PCWP < 15
PVR ≥ 3 WU
PCWP < 15
PVR < 3 WU
Many
Few
Pre-capillary PH +
Diastolic Dysfunction
DHF
Exercise
or Volume
PAH
? Treat PH
RCT
Elevated PCWP
DHF
PCWP ≥ 15
“DHF Uncertain”
Normal PCWP
PAH
Hoeper et al JACC 2009
A
100
90
Baseline
80
70
60
PA 80/31, mean 49mmHg
50
40
30
PCWP 22 mmHg
RA 15 mmHg
20
10
0
B
CI 2.3 L/min*m2, PVR 6.4 WU
100
90
Nitroprusside
80
70
60
50
PA 61/19, mean 37 mmHg
40
30
20
10
0
C
100
90
CI 2.6 L/min*m2, PVR 3.6 WU
PCWP 20 mmHg
RA 8 mmHg
Nitric Oxide
80
70
60
PA 77/27, mean 50 mmHg
50
40
30
PCWP 35 mmHg
RA 13 mmHg
20
10
0
CI 2.2 L/min*m2, PVR 3.8 WU
Boilson BA, Shirger JA, Borlaug BA. Eur J Heart Fail 2010
A
HFpEF
RA
RV
PA
Increased
RV/PA
pressures
B
Increased
PVR
Stiff
LA
Stiff LV
RA
Elevated
SVR
RV Afterload
Elevated
LV
Afterload
Elevated
HFpEF + IV Nitroprusside
RA
RV
PA
Reduced
RV/PA
pressures
C
Reduced
PVR
Stiff
LA
Stiff LV
RA
Reduced
SVR
Reduced
preload
RV Afterload
Reduced
LV
Afterload
Reduced
HFpEF + inhaled NO
RA
RV
Elevated
RV/PA
pressures
PA
Reduced
PVR
Stiff
LA
Increased
preload
RV Afterload
Reduced
Stiff LV
RA
Elevated
SVR
LV
Afterload
Unchanged
Boilson BA, Shirger JA, Borlaug BA. Eur J Heart Fail 2010
Clinical Implications
• When LVEF is normal in older pts with PH, evaluate
LV diastolic function rigorously
• In elderly pts with multiple clinical risk factors for
HFPEF, invasive cath may not be required
• When diagnostic uncertainty exists, or if pulmonary
vasodilator therapy is contemplated, cardiac cath
should be considered
• Pulmonary-specific vasodilators may worsen left
heart filling pressures in PH-HFPEF
• The high prevalence and prognostic impact of PH in
HFPEF suggests it may be a therapeutic target, but
further study is needed
Phosphodiesterase-5 Inhibition
• RCT of sildenafil (50 mg tid) vs placebo in
44 pts with HFPEF and PASP>40 mmHg
• At 6 & 12 months, sildenafil mediated
– Reduction in mPAP, RAP & PVR
– Improvement in RV & LV function
– Improvement spirometry & diffusing capacity
– Improvement in quality of life
Guazzi M et al Circulation 2011
NIH-Sponsored, Chaired by Eugene Braunwald, 7 clinical centers (competitive application)
including Duke, Baylor, Harvard, U of Utah, U of Vermont, U of M, Mayo.
Summary
• Diastolic dysfunction, vascular remodeling
and pulmonary hypertension all contribute
to the pathophysiology of HFPEF, and
represent potential therapeutic targets
• Clinicians should recognize the typical
clinical profile of patients with HFPEF,
consider cardiac catheterization in cases
of uncertainty and await results of ongoing
clinical trials
Thank you