Download Diastolic Heart Failure:

Diastolic Heart Failure:
The Other Heart Failure
(Heart Failure with Preserved EF, or HFpEF)
• Mariell Jessup MD, FAHA, FACC
• Professor of Medicine
• University of Pennsylvania
• Philadelphia, Pennsylvania
Mariell Jessup MD
• No conflicts to report
• I will discuss some off-label uses of
drugs
Outline
• Semantics/Definitions
• Epidemiology
• Pathophysiology/Mechanisms
– Diastolic Dysfunction (types)
– Ventriculo-Vascular Coupling
– Impaired systolic reserve
• Evaluation
• Treatment (current and
emerging)
A case of “old lady legs”
• 71 year old woman with well controlled
hypertension, chronic atrial fibrillation, and
diabetes was seen for her yearly check-up.
• She denied angina, palpitations or dizziness.
• Her only complaint was progressive swelling of
her legs during the day-reminding her of her
mother’s legs as she aged.
• When prompted, she did admit she was more
breathless while walking her small dog.
A case of “old lady legs”
•
•
•
•
•
BP: 150/95mmHg, HR: 95 bpm, irreg
No JVD, no carotid bruits
Lungs clear, abdomen mildly obese
Heart: soft systolic murmur, no S3+
1+ edema of both lower legs, pulses intact
• EKG: atrial fibrillation, LVH, non-specific STTW
• Echo: LVEF normal, RV normal, LA enlarged
• Labs: mild elevation of BUN, BNP elevated x 2
Semantics and Related Questions
• If not systolic HF, must it be
diastolic HF?
• Is LVEF the best determinant of
systolic HF?
• What is a “reduced” LVEF?
Heart Failure with Preserved Ejection
Fraction (HFPEF)
• HFPEF is defined by a normal or near-normal EF
(>0.50 or 0.45). This cut point does not exclude
systolic dysfunction, but is not usually associated
with heart failure symptoms in the absence of other
factors. Hence the term “preserved systolic function”.
• HFPEF is not a specific diagnosis or syndrome. It is
a constellation of findings caused by diverse
etiologies for which non-cardiac etiologies are
excluded.
• HFPEF is often equated with diastolic heart failure.
HF-pEF Epidemiology: Olmsted County, MN
•
•
•
•
~50% of all patients with HF have an LVEF ≥ 50%
Average age 74±14 years
56% female, 44% male
Relatively high rates of co-morbidities:
– Hypertension:
63%
– CAD:
53%
– AFib:
41%
– Obesity:
41%
– Diabetes:
33%
Owan TE…Redfield MM. N Engl J Med 355:251-9, 2006
Prevalence of Heart Failure
USA
10
Finland
England
(CHS) (Helsinki) (Poole)
Sweden
Den.
prevalence %
Portugal Nether.
(Vasteras) (Copen.) (Asturias) (EPICA)
9
(Rotter.)
Proportion with decreased
LV systolic function
Proportion with preserved
LV systolic function
8
7
6
Spain
8.8
8.2
7.5
6.7
6.4
5
4
4.9
3
4.2
2
1
2.1
4.8
4.2
5.1
3.1
4.5
2.9
1.7
1.5
0
age range
66-103 75-86
70-84
75
> 50
> 40
>25
55-95
mean age
78
76
75
-
60
68
65
-
Secular Trends in HF-pEF Prevalence
Associated with increasing prevalence of AFib (2941%)
and Diabetes (3236%), but no change in CAD 5959%)
Owan TE…Redfield MM. N Engl J Med 355:251-9, 2006
Audience Question #1
The prognosis for patients with
diastolic heart failure is significantly
better than for patients with systolic
heart failure.
1. True
2. False
41%
59%
Prognosis of Patients with HF-pEF
After 1st Hospitalization
Overall
Bhatia RS...Liu PP.
Owan TE…Redfield MM.
N Engl J Med 355:260-9, 2006
N Engl J Med 355:251-9, 2006
Effect of LVEF on
In-Hospital Outcomes for ADHF
• Data from >100,000 hospitalizations of the Acute
Decompensated Heart Failure Registry (ADHERE)
• CHF-pEF present in 50.4% of patients
• Patients with CHF-pEF were older, women, and
hypertensive; less likely to have prior MI
• In-hospital mortality was 2.8% for patients with
CHF-pEF and 3.9% for patients with reduced EF
Yancy CW et al. (ADHERE). J Am Coll Cardiol 47:76-84, 2006
Effect of LVEF on
Post-Hospital Outcomes for ADHF
• The OPTIMIZE Registry examined 90-day follow
up of 20,118 patients admitted with HF and
LVEF<40% and 21,149 patients with HF-pEF
• There were similar rates of mortality (9.5% vs.
9.8%) and rehospitalization (29.2% vs. 29.9%)
among patients with HF-pEF and HF with
systolic dysfunction, respectively
Fonarow G et al. J Am Coll Cardiol 50:768-77, 2007
Differences and Similarities Between
Preserved EF and Reduced EF Heart Failure
Differences
• More women
• Older patients
• More hypertension (past
and current)
• Less CAD, especially MI
• More CKD
• Smaller, thicker LV
Similarities
• Race
• Diabetes
• Tobacco
• Lipids
• Obesity
• Atrial fibrillation (?)
Pathophysiology of HF-pEF:
Cardiac Morphology & Hemodynamics
HF with ↓ LVEF
HF-pEF
↑
↑
Normal
↑ or normal
↑
LV Morphology
(Normal:
)
LVEDV
LV Mass
Relative Wall
Thickness
LVEF
Left Atrium
LVEDP
↓
↓
Dilated
↑
Normal
Dilated
↑
Audience Question #2
The primary pathophysiological
mechanism driving the syndrome of
HF-pEF is impaired diastolic filling of
the left ventricle
1. True
2. False
62%
38%
Why Do HFPEF Patients Decompensate?
(Potential “targets”)
•
•
•
•
•
•
•
•
Excess salt (or discontinuation of diuretic)
Worsening hypertension
Medications: NSAIDs, CCBs, thiazolidinediones
Atrial fibrillation
Iatrogenic volume overload
Myocardial ischemia
Worsening renal function
Anemia
Pathophysiology of HF-pEF
I. Focus on Diastolic Dysfunction
Pathophysiology of HF-pEF:
Diastolic Dysfunction
HF-PEF (N=47)
Controls (N=10)
71±11
73±13
103±22
115±9
LVEDP, mmHg
25±6
8±2
Tau, msec
59±14
35±10
PSR, mmHg
7±5
0
Heart Rate, bpm
LVEDV, ml
Zile MR…Gaasch WH. N Engl J Med 350:1953-9, 2004
Diastolic Function in HF-pEF
vs. Hypertensive LVH (H-LVH)
Age
Control
(56)
65±11
H-LVH
(40)
67±10
HF-pEF
(37)
65±10
LVEDV
111±24
112±32
115±33
E/A ratio
1.1±0.3
0.9±0.3
1.0±0.4
E-decel time
219±42
247±64 *
257±112
78±11
96±17†
85±22
E/E’ ratio
8.4±2.2
11±4.5†
15±5.3*†
Dias Fxn Grade
0.6±0.9
1.1±0.9
1.4±0.9
IVRT
Melenovsky V…Kass DA. J Am Coll Cardiol 49:198-207, 2007
NT-proBNP levels in diastolic dysfunction are elevated
and correlate with the severity of disease
Tschope C et al. Eur Heart J 26:2277-2284, 2005
Diagnosis of HF-pEF
European Society of Cardiology Algorithm
Symptoms/Signs of HF
+
LVEF>50% & LVEDVI>97 mL/m2
+
Evidence of Abnormal LV relaxation, filling or stiffness
or
Catheterization
mPCW >12 mmHg
LVEDP >15 mmHg
Tau > 48 ms
or
TD
E/E’>15
or
TD
8<E/E’<15
+
BNP>200
Paulus WJ et al. Eur Heart J 28:2539-50, 2007
TD
8<E/E’<15
+
Abnormal
Blood flow
Doppler
Pathophysiology of HF-pEF
I. Focus on Arterial Stiffening
Effect of Normal Conduit Vessel Elasticity
Energy Storage in Elastic Materials
The amount of energy stored in
materials can be determined by
calculating the area under the
stress-strain curve, which is shown
for the brittle material, stiff
material, and compliant material.
A compliant material will store
more energy than a brittle
material for a given value of
applied stress, S.
Saltzman WM. Biomedical Engineering: Bridging Medicine and Technology.
(New York: Cambridge Univ Press, 2009)
Vessel Composition Across the
Circulatory System
• Relatively high elastic tissue content in large conduit
arteries favors their ability to absorb and release energy
15-2
Effect of Reduced Conduit Vessel Elasticity
Pathophysiology of HF-pEF:
Arterial Stiffness and Wave Reflections
• 336 consecutive Pts hospitalized for LHC & EF>50%
• Invasive and noninvasive assessments of diastolic
function
• Invasive and noninvasive assessments of arterial
stiffness and wave reflection
• Arterial pulse wave velocity (an index of vascular
stiffness) was the most powerful predictor of ↓E’ and
↑LVEDP
• In multivariate analysis, female gender & higher
pulse wave velocity were independently associated
with ↑symptoms
Weber T et al. Am J Hypertens 21:1194-1202, 2008
E’ septal (cm/s)
LVEDP (mmHg)
I
II
III .
NYHA:
I
II
III .
NYHA:
I
II
III .
I
II
III .
Augmentation Index
Pulse Wave Velocity (m/s)
NYHA:
NYHA:
Weber T et al. Am J Hypertens 21:1194-1202, 2008
Central Aortic Stiffness and HF-pEF
Desai AS…Creager MA. J Cardiac Failure 15:658-64, 2009
Pathophysiology of HF-pEF
I. Focus Impaired Contractile Reserve
Exercise Responses in HF-pEF vs. Normal:
Impairment in the Frank-Starling Mechanism
Kitzman DW…Sullivan MJ. J Am Coll Cardiol 17:1065-72, 1991
Exercise Responses in H-LVH vs. HF-pEF
Differences at Peak Exercise
- HTNsive LVH
- HF-pEF
Borlaug BA…Kass DA. Circulation 114:2138-47, 2006
Decreased Contractile Reserve in HF-pEF
•
•
Dobutamine Echo (max 16 g/kg/min)
10 Pts with HF-pEF & 9 controls
(age, sex matched)
LVEF Reserve
Dynamic Strain
Rate Reserve
Lateral Longitudinal
Velocity Reserve
Norman HS…Sweitzer NK. J Card Fail 17:301-8, 2011
Implications of increased LV & Arterial Stiffening
Abnormality
Consequence
Clinical Relevance
↑ LV Stiffness
Exaggerated ↑ LVEDP
Reduced SV reserve
Increased sensitivity to
volume shifts
Impaired Ex Tolerance
Impaired Coronary
Reserve
Increased predilection to
ischemia
Exaggerated ↑ BP
Increased predilection to
ischemia
Impaired Ex Tolerance
↑ Arterial
Stiffness
Increased afterload
Reduced Capacitance
Increased sensitivity to
volume shifts
Audience Question #3
Which of the following reduces
mortality among patients with HFpEF?
1. Beta-blockers
2. ACE-inhibitors
3. Angiotensin receptor blockers
4. Cardiac resynchronization therapy
5. None of the above
22%
26%
8%
10%
32%
Treating Diastolic Heart Failure
The Theory
hundreds of
papers!
The Evidence
virtually none!!
HF Due to Diastolic Dysfunction
Potential Treatment Targets
 LV volume & edema:
diuretics, salt, avoid NSAIDS
 Rx systolic HTN:
diuretics, others
 Reverse LVH:
ACEI, ARB, most anti-HTN
 Prevent fibrosis:
ACEI, ARB, aldo blockers
 Prevent ischemia:
BB, CA, nitrates
 HR, prevent AF:
BB, some CA, ACEI, ARB
 Enhance relaxation:
no drugs currently available
 vascular compliance:
product
?RAAS I, glycation endcrosslink breakers
Two phases
• Prevention – “Stage A”
–
–
–
–
–
Blood pressure control
Coronary disease/ischemia prevention
Obesity
Diabetes
“Metabolic Syndrome”
• Treatment – “Stage B, C and D”
Incidence of Heart Failure (%)
Prevention of Heart Failure in
SHEP
8
RR=0.51
95% CI 0.37-0.71
6
4.4%
P<0.001
4
2.3%
2
0
Placebo
Active Rx
(Diuretic/BB)
Kostis JB et al. JAMA. 1997;278:212-216.
CHARM-Preserved - Patient Disposition
3025 patients randomized
NYHA class II-IV
LVEF >40%
2 patients with no data
Candesartan
n=1514
Lost to
follow-up
n=2
Completed study
n=1512
Placebo
n=1509
Lost to
follow-up
n=1
Completed study
n=1508
Median follow-up: 36.6 months
NYHA, New York Heart Association; LVEF, left ventricular ejection fraction.
Yusuf S et al. Lancet. 2003;362:777-781.
CHARM-Preserved
Baseline Characteristics
Alternative
n=2028
Mean age (yrs)
Women (%)
NYHA class (%)
II
III
IV
Mean LVEF (%)
Medical history (%)
Myocardial infarction
Diabetes
Hypertension
Atrial fibrillation
Added
n=2548
Preserved
n=3023
Overall
n=7599
67
32
64
21
67
40
66
32
48
49
4
30
24
73
3
28
61
38
2
54
45
52
3
39
62
27
50
25
56
30
48
26
44
28
64
29
53
28
55
27
NYHA, New York Heart Association; LVEF, left ventricular ejection fraction.
McMurray J et al. Eur J Heart Fail. 2003;5:261-270.
CHARM-Preserved
Baseline Medications
Alternative
n=2028
Added
n=2548
Preserved
n=3023
Overall
n=7599
ACE inhibitor
0
100
19
41
Beta-blocker
55
55
56
55
Diuretic
86
90
75
83
Spironolactone
24
17
12
17
Digitalis
46
58
28
43
Aspirin
58
52
58
56
Lipid-lowering
42
41
42
42
Baseline therapy (%)
McMurray J et al. Eur J Heart Fail. 2003;5:261-270.
CHARM-Preserved: Primary outcome
CV death or CHF hospitalization
30
25
20
15
10
5
0
%
Placebo
366 (24.3%)
333 (22.0%)
Candesartan
HR 0.89 (95% CI 0.77-1.03), p=0.118
0
Number at risk
Candesartan 1514
Placebo
1509
1
2
1458
1441
1377
1359
3 3.5years
833
824
182
195
CHARM – Preserved
Conclusions
• Among patients with symptomatic heart
failure and an ejection fraction >40%,
treatment with the ARB candesartan was
associated with a non-significant reduction
in the primary endpoint of cardiovascular
death or heart failure hospitalizations
• Candesartan has a moderate impact in
preventing admissions for CHF among
patients who have heart failure and LVEF
higher than 40%.
Perindopril in elderly people with chronic heart
failure (PEP-CHF)
Cleland J G et al. Eur Heart J 2006;27:2338-2345
31% RRR in year 1
P=0.55
One-year outcomes in PEP-CHF
perindopril vs. placebo
End point
Perindopril,
n=424 (%)
Placebo, n=426
(%)
p
All-cause mortality or
unplanned HF
hospitalization
10.8
15.3
0.055
Unplanned HF
hospitalization
8.0
12.4
0.033
All-cause mortality
4.0
4.5
NS
Cleland JGF. World Congress of Cardiology 2006; September 3,
2006; Barcelona, Spain.
PEP-CHF Conclusions
• The ACE-Inhibitor perindopril improved
symptoms and exercise capacity and led to
fewer hospitalizations for heart failure in the
first year
• There was no improvement in total
mortality
I-PRESERVE: Entry Criteria
Age 60 years
Current HF symptoms
LVEF 0.45
NYHA class II - IV
 CHF hosp. 6 months
NYHA Class III/IV
 CXR congestion
 ECG (LVH, LBBB)
 Echo (LVH, LAE)
Key Exclusions: SBP >160 mm Hg; prior EF <40%; ACS or stroke ≤
3m, hypertrophic or restrictive CM, pericardial or valvular disease,
significant pulmonary disease, creatinine >2.5, Hb <11
I-PRESERVE: Outcomes
• Primary endpoint: All cause mortality and protocolspecified CV hospitalizations (for heart failure, MI,
unstable angina, stroke, ventricular or atrial
arrhythmia).
• Secondary endpoints:
– All cause mortality
–
–
–
–
–
CV death
HF death or HF hospitalization
CV death, MI or stroke
QoL (Minnesota)
Change in BNP levels
I-PRESERVE: Patient Characteristics
Cohort & Epidemiological
Studies
I-PRESERVE
(n=4,128)
Age, yr
75
72
Women
65-70%
60%
60%
59%
80-90%
88%
<20%
23%
Atrial fibrillation
20-30%
29%
Diabetes
20-30%
27%
EF
Hypertension
Prior MI
I-PRESERVE: Primary Endpoint
Death or protocol specified CV hospitalization
HR (95% CI) = 0.95 (0.86-1.05)
Placebo
Log-rank p=0.35
Primary Events (%)
Cumulative Incidence of
40 -
30 -
Irbesartan
20 -
10 -
00
No. at Risk
Irbesartan
Placebo
6
12
18
24
30
36
42
48
Months from Randomization
2067 1929 1812 1730 1640 1569 1513 1291 1088
2061 1921 1808 1715 1618 1539 1466 1246 1051
54
60
816
776
497
446
I-PRESERVE: Conclusions
• In I-PRESERVE, HF-PEF patients experienced substantial
mortality and cardiovascular morbidity.
• Irbesartan did not reduce the primary endpoint of death and
protocol-specified CV hospitalizations, nor did it significantly
benefit prespecified secondary endpoints.
• The results are consistent with the two previous trials in
patients with HF-PEF that did not demonstrate a positive
effect.
• For this large group of patients constituting half of all heart
failure patients, there continues to be no specific evidencebased therapy.
• In order for this field to move forward, a better understanding
of the mechanisms underlying this syndrome and additional
potential targets for treatment are required.
Randomized Trials in HF-pEF
Trial Name
CHARMPreserved1
Drug (Class)
Outcome
[# Pts]
Candesartan (ARB) No Δ Mortality
[3,023]
↓ Hospitalization
I-Preserved2 Irbesartan (ARB)
[4,128]
PEP-CHF
Perindopril (ACE-I)
[384]
1 Yusef
No Δ Mortality
No Δ Hospitalization
No Δ Mortality
↓ Hospitalization (1 yr)
S et al. Lancet 362:777–81, 2003
2 Massie B et al. N Engl J Med 359:2456-2467
3 Cleland JG et al. Eur Heart J 27:2338-45, 2006
TOPCAT
• TOPCAT is a multi-center, international,
randomized, double blind placebo-controlled
trial of the aldosterone antagonist,
spironolactone, in 4500 adults with heart
failure and left ventricular ejection fraction of
at least 45%, recruited internationally from
over 200 clinical centers in the US, Canada,
Russia, Republic of Georgia, Argentina, and
Brazil.
TOPCAT - Endpoints
• The primary endpoint is a composite of
cardiovascular mortality, aborted cardiac
arrest or hospitalization for the management
of heart failure.
• Secondary endpoints include all-cause
mortality, new onset of diabetes mellitus or
atrial fibrillation, and quality of life.
DIG ancillary Trial
• Randomized 988 patients with chronic heart
failure who were in sinus rhythm and had
LVEFs greater than 45%.
• No differences between mortality in the
digitalis and placebo groups
• Secondary endpoint of death or
hospitalization for worsening heart failure,
trend toward benefit when sinus rhythm is
present driven by decreased hospitalizations.
Digoxin
• Trend toward more hospitalizations for nonheart failure causes, resulting in no
significant difference in all-cause
hospitalizations
• Therefore, digoxin has at most a very
limited role in the management of patients
in normal sinus rhythm
N. Engl. J. Med. 336 (1997), pp. 525–533.
SENIORS Trial
• Evaluated nebivilol (vasodilating Betablocker) in patients > 70 years with heart
failure
• About 20% had EF > 35%
• Appeared to be beneficial but need more
data about the subgroup with preserved EF
• Will need another trial specific to HFpEF
Eur. Heart J. 26 (2005), pp. 215–225
COHERE - Hospitalizations before and after
Carvedilol, by EF
HF Hosp. prior yr
40
HF Hosp. 1 yr f/u
*
35
P = 0.001 vs. prior year
30
% of Patients
25
20
*
15
*
10
*
*
5
0
<21
21-30
Ejection Fraction
Massie BM et al. AJC 2007; 99: 1263-8
31-40
>40
Common Sense HF-pEF Management
• Address underlying diseases (CAD, HTN, renal
dysfunction, DM, obesity & sleep apnea)
• Avoidance of excessive tachycardia – especially
Afib with rapid ventricular response
• Careful volume status management (education,
weights, BNP tracking, implanted monitoring
devices)
Patients With Heart Failure and Normal Left
Ventricular Ejection Fraction
Normal Left Ventricular Ejection Fraction
I IIa IIb III
Physicians should control systolic and diastolic
hypertension in patients with HF and normal LVEF, in
accordance with published guidelines.
NO CHANGE
I IIa IIb III
Physicians should control ventricular rate in patients with
HF and normal LVEF and atrial fibrillation. NO CHANGE
I IIa IIb III
Physicians should use diuretics to control pulmonary
congestion and peripheral edema in patients with HF
and normal LVEF.
NO CHANGE
ESC 2005 Chronic HF Guidelines
Emerging Strategies for
Pathophysiological Targeting for HF-pEF
Mechanism
Approach
Possible Agents
Abnormal LV
Relaxation
Increase myocyte Ca2+
uptake rates
SERCA agonists
Ranolazine
PDE-5 inhibitors
Ivabradine
Slow heart rate
Increased LV
Stiffness
↓ Collagen X-links
↓ AGEs
↓ fibrosis
TGFβ inhibitors
Aminoguanidine
Alagebrium
Aldosterone Antag.
↑ Vascular
Stiffness
↓ Atherosclerosis
↓ Aortic Stiffness
Statins
Nitrates
Aminoguanidine
Alagebrium
↓ Vascular
Capacitance
Improved volume
management
Implantable monitors
(± interventions)
Summary
• HF-pEF accounts for ~50 of HF, is increasingly
prevalent, and carries a prognosis that is nearly
as poor as for patients with “systolic HF”
• Patients with HF-pEF usually have LV diastolic
function abnormalities, however, these
abnormalities are also present in elderly and
hypertensive patients without heart failure
• Coexistant increases in arterial stiffness, impaired
systolic reserve and co-morbid factors like atrial
fibrillation, HTN and CAD contribute to HF-pEF
• Ang-II antagonists may reduce hospitalization in
HF-pEF, but do not affect mortality.
Conclusions
• Combined increases in LV and arterial stiffness
likely account for the exaggerated volume
sensitivity of patients with HF-pEF
• Differences in pathophysiology and heterogeneity
among patients with HF-pEF may account for
underwhelming responses to therapies that have
been effective for patients with systolic HF
• Treatment strategies to achieve improved volume
management and target ventricular and vascular
abnormalities will be required to address the
increasing prevalence of HF-pEF