heart failure with reduced ejection fractionheart failure with reduced ejection fraction state of...
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HEART FAILURE WITH
REDUCED EJECTION FRACTION
STATE OF THE ART
Felix J. Rogers, DO, FACOI
February 28, 2018
Heart Failure Management
If your only tool is a hammer…• Models of pharmacologic management
• Volume overload
A Traditional Model for
Chronic Heart Failure
A Clinical ModelFrom Mann, DL Circulation 1999; 100: 999-1008
A Comprehensive ModelFrom Mann, DL Circulation 1999; 100: 999-1008
The New Paradigm, 2008
Electromechanical therapy
• AICD
Restoration of myocardial function
• Cardiac resynchronization therapy
• Restoration of myocardial twist
• Surgical approaches to remodeling
• Prevention of sudden death
Bardy GH et al. N Engl J Med 2005;352:225-237.
Kaplan–Meier Estimates of Death from Any Cause for the Prespecified Subgroups of Ischemic CHF (Panel A) and Nonischemic CHF (Panel B).Amiodarone vs AICD in HFrEF
CRT for HFrEF,
CARE HF Study.
Cleland JG et al. N Engl J Med 2005;352:1539-1549.
Kaplan–Meier Estimates of the Time to the Primary End Point (Panel A) and the Principal Secondary Outcome (Panel B).
CARE – HF Trial of CRT vs medical therapy in HFrEF
New models for management of HF
• Pharmacologic
• Electromechanical
• Mechanical
• Systemic
New models for management of HF
• Pharmacologic• Sacubritil/Valsartan
• Beta blocker
• Diuretic
• Electromechanical• AICD
• CRT + AICD
• Mechanical• LVAD
• Transplant
• Systemic• Sleep apnea
• Exercise
New models for management of HF
• Pharmacologic• Sacubritil/Valsartan
• Beta blocker
• Diuretic
• Anticoagulation
• Electromechanical• AICD
• CRT + AICD
• Pulmonary vein isolation for atrial fibrillation
• Mechanical• LVAD
• Systemic interventions: • Detection of CAD, Anemia, Sleep apnea
Not covered today
• Ivradabine
• Valvular interventions
• TAVR
• TAMR
• TATR
• Coronary artery revascularization
• Heart failure with mid-range ejection fraction (HFmrEF)
Not covered today
• Ivradabine
• Valvular interventions
• TAVR
• TAMR
• TATR
• Coronary artery revascularization
• Heart failure with mid-range ejection fraction (HFmrEF)
• Now, on to
Pharmacologic therapy
15
Suppress deleterious
effects of RAAS
Enhance the beneficial
effects of endogenous
compensatory peptides
Sacubitril/Valsartan
1. Kemp CD, Conte JV. Cardiovasc Pathol. 2012;21(5):365-371. 2. Mangiafico S et al. Eur Heart J. 2013;34:886-893. 3. Nathisuwan S, Talbert RL. Pharmacotherapy. 2002;22:27-42. 4. Hasenfuss G, Mann DL. Pathophysiology of heart failure. In: Mann DL et al, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia, PA: Elsevier; 2015. 5. Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.
SNS1,4
HF SYMPTOMS &
PROGRESSION
Epinephrine
Norepinephrineα1, β1, β2
receptors
VasoconstrictionRAAS activity
Heart rateContractility
Endogenous Compensatory
Peptides2-4
VasodilationBlood pressureSympathetic toneNatriuresis/diuresisVasopressinAldosteroneFibrosisHypertrophy
NPs, Bradykinin, ADM
Sacubitril/
valsartan5
RAAS1,2
VasoconstrictionBlood pressure
Sympathetic toneVasopressinAldosteroneHypertrophy
Fibrosis
Ang II AT1R
Neprilysin
Inhibitor
VasodilationBlood pressureSympathetic toneNatriuresis/diuresisVasopressinAldosteroneFibrosisHypertrophy
NPs, Bradykinin, ADM
Endogenous Compensatory
Peptides2-4
+
ARB
RAAS1,2,4
VasoconstrictionBlood pressure
Sympathetic toneVasopressinAldosteroneHypertrophy
Fibrosis
Ang II AT1R
Effects of Sacubitril/valsartan in HFrEF
Slide has animation
NPR-A, NPR-B, B2, calcitonin
receptor-like receptor
16
Sacubitril/ValsartanEffect on BNP and NT-proBNP
BNPs, brain natriuretic peptides; NT-proBNP, N-terminal of the prohormone brain natriuretic peptide.aVasoactive peptides include the NPs (atrial NPs, BNPs, C-type NPs), adrenomedullin, and bradykinin.Modified from Vardeny O et al. Clin Pharmacol Ther. 2013;94:445-448.
Inactive
fragments
⬆ Myocardial
wall tension
in HF
Inactive
(inert) marker
of HF
Vasoactive
peptidea with
cardioprotective
effects
BNP NT-proBNP
⬆ proBNP secretion
NeprilysinSacubitril/
valsartanNeprilysin inhibition has
no effect on NT-proBNP
Slide has animation
Sacubitril/Valsartan
Increases BNP Levels
ENTRESTO®
Effects on Neprilysin and RAAS
cGMP=cyclic guanosine monophosphate; RAAS=renin-angiotensin-aldosterone
system; SNS=sympathetic nervous system
Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Schrier & Abraham. N Engl J Med 2009;341:577–85;Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
Increases effects of endogenous
compensatory peptides
Vasodilation
Natriuretic and diuretic effects
Proliferation
Hypertrophy
SNS outflow/sympathetic tone
Aldosterone secretion
Detrimental effects of vascular
remodeling
Suppressing RAAS-mediated
effects
Vasoconstriction
Sodium and water retention
Ventricular hypertrophy/remodeling
Aldosterone secretion
Cardiac fibrosis
Sympathetic tone
Systemic vascular resistance
ENTRESTO
17
Neprilysin Inhibition RAAS Suppression
PARADIGM-HF TRIAL
KEY FINDINGS
2 weeks Median duration of follow-up: 27 months
Randomization
Enalapril 10 mg BID
Sac/val 97/103 mg BID
Sac/valb
97/103 mg BID
On top of standard HF therapy,
excluding ACEIs and ARBs3
Testing tolerability to target doses of enalapril and sac/val
Sac/valb
49/51 mg BID
Enalaprila
10 mg BID
1–2 weeks 2–4 weeks
Single-blind run-in period
Double-Blind Randomized Treatment Period
19
Primary outcome: To demonstrate superiority of sacubitril/valsartan over enalapril in reducing composite of death from CV causes or a first hospitalization for HF
PARADIGM-HFStudy Design
1. Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015. 2. McMurray JJ et al. Eur J Heart
Fail. 2013;15(9):1062-1073. 3. McMurray JJ et al. N Engl J Med. 2014;371(11):993-1004.
N=8442 patients with chronic HF (NYHA class II–IV with LVEF ≤40%) and elevated BNP
BID, twice daily; BNP, brain natriuretic peptide; NYHA, New York Heart Association. aEnalapril 5 mg BID for 1–2 weeks followed by enalapril 10 mg BID was an optional starting run-in dose for patients treated with ARBs or with a low dose of ACEI.bDosing in clinical trials was based on the total amount of both components of sac/val; 24/26 mg, 49/51 mg, and 97/103 mg were referred to as 50 mg, 100 mg,
and 200 mg, respectively. Sac/val was formerly known as LCZ696 in clinical trials.
Phase 3 Trial to Examine the Efficacy of Sacubitril/Valsartan vs Enalapril in Patients With HFrEF1,2
A 36 hour washout was required after single blind enalapril run-in and also at end of entresto single blind run-in
prior to being randomized
20
PARADIGM-HFBaseline Characteristics
BPM, beats per minute; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; IQR, interquartile range; SBP, systolic blood pressure. *Mean ± standard deviation, unless stated.McMurray JJ et al. N Engl J Med. 2014;371:993-1004.
Characteristic* Sac/Val (N=4187) Enalapril (N=4212)
Age, years 63.8 ± 11.5 63.8 ± 11.3
Female, n (%) 879 (21.0) 953 (22.6)
Ischemic cardiomyopathy, n (%) 2506 (59.9) 2530 (60.1)
LVEF (%) 29.6 ± 6.1 29.4 ± 6.3
NYHA functional class, n (%)
II
III
2998 (71.6)
969 (23.1)
2921 (69.3)
1049 (24.9)
SBP, mm Hg 122 ± 15 121 ± 15
Heart rate, BPM 72 ± 12 73 ± 12
NT-proBNP, median, pg/mL (IQR) 1631 (885–3154) 1594 (886–3305)
BNP, median, pg/mL (IQR) 255 (155–474) 251 (153–465)
History of DM, n (%) 1451 (34.7) 1456 (34.6)
Treatments at randomization, n (%)
Diuretics
Digitalis
Beta-blockers
MRAs
ICD
CRT
3363 (80.3)
1223 (29.2)
3899 (93.1)
2271 (54.2)
623 (14.9)
292 (7.0)
3375 (80.1)
1316 (31.2)
3912 (92.9)
2400 (57.0)
620 (14.7)
282 (6.7)
21
PARADIGM-HFPrimary Endpoint: Time to First Occurrence of CV Death or HF Hospitalization
CI, confidence interval; HR, hazard ratio. McMurray JJ et al. N Engl J Med. 2014;371:993-1004.
Enalapril
Sac/val
1.0
0.6
0.4
0.2
0
0 180 360 540 720 900 1080 1260
1117 events
914 events
HR: 0.80 (95% CI: 0.73–0.87)
P<0.001
20% Relative Risk Reduction
Cum
ula
tive
Pro
bab
ilit
y o
f th
e
Com
bin
ed E
ndpoin
t of
CV
Dea
th o
r
HF
Hosp
ital
izat
ion
No. at risk
Sac/val 4187 3922 3663 3018 2257 1544 896 249
Enalapril 4212 3883 3579 2922 2123 1488 853 236
Days Since Randomization
The difference in favor of sacubitril/valsartan was seen early in the trial and at each
interim analysis
22
PARADIGM-HFSummary of Key Findings
aAnalyses of the components of the primary composite endpoint were not prospectively planned to be adjusted for multiplicity.bIncludes subjects who had HF hospitalization prior to death.Entresto (sacubitril/valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2015.
22
Endpoint
Sac/Val
N=4187
n (%)
Enalapril
N=4212
n (%)
HR (95% CI) P Value
Primary composite endpoint of
CV death or HF hospitalization
CV death as first event
HF hospitalization as first event
914 (21.8)
377 (9.0)
537 (12.8)
1117 (26.5)
459 (10.9)
658 (15.6)
0.80 (0.73–0.87) <0.0001
Number of patients with eventsa
CV deathb
HF hospitalizations
558 (13.3)
537 (12.8)
693 (16.5)
658 (15.6)
0.80 (0.71–0.89)
0.79 (0.71–0.89)
All-cause mortality 711 (17.0) 835 (19.8) 0.84 (0.76–0.93) 0.0009
PARADIGM-HFProspectively defined safety events
• Fewer patients in the Entresto group than in the enalapril group stopped their study
medication because of an AE (10.7 vs 12.3%, p=0.03)
Event, n (%)
Entresto
(n=4187)
Enalapril
(n=4212) p-value‡
Hypotension
Symptomatic 588 (14.0) 388 (9.2) <0.001
Symptomatic with SBP <90 mmHg 112 (2.7) 59 (1.4) <0.001
Elevated serum creatinine
≥2.5 mg/dL 139 (3.3) 188 (4.5) 0.007
≥3.0 mg/dL 63 (1.5) 83 (2.0) 0.10
Elevated serum potassium
>5.5 mmol/L 674 (16.1) 727 (17.3) 0.15
>6.0 mmol/L 181 (4.3) 236 (5.6) 0.007
Cough 474 (11.3) 601 (14.3) <0.001
Angioedema (adjudicated by a blinded expert committee)
No treatment or use of antihistamines only 10 (0.2) 5 (0.1) 0.19
Catecholamines or glucocorticoids without hospitalization 6 (0.1) 4 (0.1) 0.52
Hospitalized without airway compromise 3 (0.1) 1 (<0.1) 0.31
Airway compromise 0 0 ---
McMurray, et al. N Engl J Med 2014; 371: 993-1004
23
PARADIGM-HF Effects of ENTRESTO® on BNP
Wk
0
Wk
4
Mth
8
Wk
-10
Wk
-8
Enalapril
Run-in*
Entresto
Run-in* Enalapril
Entresto
*Patients in both groups received the same single-blind treatment
Geo
met
ric
Mea
n
(nm
ol/
L)
Packer M et al. Circulation. 2014;131:54–61.
"BNP, but not NTproBNP, is a neprilysin substrate, and therefore BNP levels will increase as levels of
active drug increase; whereas levels of NTproBNP will show the effects of the drug on the heart"
Entresto ® (sacubitril/valsartan) [full prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; July 2015.
24
PARADIGM-HF: Effects of ENTRESTO® on NT-proBNP
Enalapril
Entresto
Wk
0
Wk
4
Mth
8
Wk
-10
Wk
-8
*Patients in both groups received the same single-blind treatment
Geo
met
ric
Mea
n
(nm
ol/
L)
Enalapril
Run-in*
Entresto
Run-in*
Packer M et al. Circulation. 2014;131:54–61.
"BNP, but not NTproBNP, is a neprilysin substrate, and therefore BNP levels will increase as levels of
active drug increase; whereas levels of NTproBNP will show the effects of the drug on the heart"
Entresto ® (sacubitril/valsartan) [full prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; July 2015.
25
2016 ACC/AHA/HFSA Focused UpdatePharmacological Treatment for Stage C HFrEF: Recommendations
COR LOE Recommendations
I
ACE: A The clinical strategy of inhibition of the renin-angiotensin
system with ACE inhibitors (Level of Evidence: A), OR
ARBs (Level of Evidence: A), OR ARNI (Level of
Evidence: B-R) in conjunction with evidence-based beta
blockers, and aldosterone antagonists in selected
patients, is recommended for patients with chronic
HFrEF to reduce morbidity and mortality.
ARB: A
ARNI: B-R
Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB
or ARNI
“In ARNI, an ARB is combined with an inhibitor of neprilysin, an enzyme that degrades natriuretic peptides,
bradykinin, adrenomedullin, and other vasoactive peptides. In an RCT that compared the first approved ARNI,
valsartan/sacubitril, with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either
ACE inhibitor or ARB, the ARNI reduced the composite endpoint of cardiovascular death or HF hospitalization
significantly, by 20%. The benefit was seen to a similar extent for both death and HF hospitalization and was
consistent across subgroups. The use of ARNI is associated with the risk of hypotension and renal insufficiency
and may lead to angioedema, as well.”
ARNI, angiotensin receptor-neprilysin inhibitor
Yancy CW, et.al. , 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update
of the 2013 ACCF/AHA Guideline for the Management of Heart Failure, Journal of the American College of Cardiology (2016),
doi: 10.1016/ j.jacc.2016.05.011.
2016 ACC/AHA/HFSA Focused Update
Pharmacological Treatment for Stage C HFrEF: Recommendations
COR LOE Recommendations
I ARNI: B-R
In patients with chronic symptomatic HFrEF NYHA class
II or III who tolerate an ACE inhibitor or ARB, replacement
by an ARNI is recommended to further reduce morbidity
and mortality.
Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or
ARB or ARNI (cont’d)
“In patients with mild-to-moderate HF (characterized by either [1] mildly elevated natriuretic peptide levels, BNP
[B-type natriuretic peptide] >150 pg/mL or NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥600 pg/mL;
or [2] BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL with a prior hospitalization in the preceding 12 months) who
were able to tolerate both a target dose of enalapril (10 mg twice daily) and then subsequently an ARNI
(valsartan/sacubitril, 200* mg twice daily, with the ARB component equivalent to valsartan 160 mg),
hospitalizations and mortality were significantly decreased with the valsartan/sacubitril compound compared with
enalapril.”
*Dosing in clinical trials was based on the total amount of both components of sacubitril/valsartan, i.e., 24/26 mg, 49/51 mg, and
97/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively.
ARNI, angiotensin receptor-neprilysin inhibitor
Yancy CW, et.al. , 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update
of the 2013 ACCF/AHA Guideline for the Management of Heart Failure, Journal of the American College of Cardiology (2016),
doi: 10.1016/ j.jacc.2016.05.011.
2016 ACC/AHA/HFSA Focused Update
Pharmacological Treatment for Stage C HFrEF: Recommendations
COR LOE Recommendations
III: Harm B-R
ARNI should not be administered concomitantly with
ACE inhibitors or within 36 hours of the last dose of an
ACE inhibitor.
III:
HarmC-EO
ARNI should not be administered to patients with a
history of angioedema.
Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB
or ARNI (cont’d)
• Oral neprilysin inhibitors when used in combination with ACE inhibitors can lead to angioedema -
concomitant use is contraindicated and should be avoided
• An ARNI should not be administered within 36 hours of switching from or to an ACE inhibitor.
• In patients with a history of angioedema there is a concern that treatment with an ARNI will increase
the risk of a recurrence of angioedema
ARNI, angiotensin receptor-neprilysin inhibitor
Yancy CW, et.al. , 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update
of the 2013 ACCF/AHA Guideline for the Management of Heart Failure, Journal of the American College of Cardiology (2016),
doi: 10.1016/ j.jacc.2016.05.011.
Stroke risk in patients with HFrEF
• Meta-analysis of 4 trials. 22,904 patients with myocardial
infarction without A Fib
• Follow up of 1.9 years. 660 patients had a stroke. (2.9%)
• Final stroke risk model
• Older age
• Killip Class 3 or 4 MI
• eGFR < 45 ml/min/1.73 m2
• Hypertension history
• History of previous stroke
João Pedro Ferreira et al. JACC 2018;71:727-735
2018 American College of Cardiology Foundation
João Pedro Ferreira et al. JACC 2018;71:727-735
2018 American College of Cardiology Foundation
Pulmonary vein isolation for HF + AF
• Atrial fibrillation and heart failure commonly occur
together, with atrial fibrillation increasing the risk for stoke,
hospitalization for heart failure and death.
Pulmonary vein isolation for HF + AF
• Atrial fibrillation and heart failure commonly occur
together, with atrial fibrillation increasing the risk for stoke,
hospitalization for heart failure and death.
• Rhythm control with antiarrhythmic drugs is not superior
to rate control in patients with atrial fibrillation.
Pulmonary vein isolation for HF + AF
• Atrial fibrillation and heart failure commonly occur
together, with atrial fibrillation increasing the risk for stoke,
hospitalization for heart failure and death.
• Rhythm control with antiarrhythmic drugs is not superior
to rate control in patients with atrial fibrillation.
• Catheter ablation is well-established as a treatment for
atrial fibrillation in patients with normal LV function, and
there is some evidence of benefit in patients with heart
failure.
CASTLE-AF. Catheter ablation vs standard
conventional therapy in patients with LV dysfunction
and atrial fibrillation.
• Patients with paroxysmal or chronic atrial fibrillation and
• LV EF < 35%
• AICD
• Standard therapy for HF
Randomized to:
• Pulmonary vein isolation - 179 patients
• Medical therapy (rate/rhythm control) - 184 patients
Kaplan–Meier Curves Comparing Survival Free of the Primary End Point (Death from Any
Cause or Admission for Worsening Heart Failure) and Its Two Components in the Two Trial Groups.
Marrouche NF et al. N Engl J Med 2018;378:417-427
Outcomes of CASTLE-AF. NEJM Feb 1, 2018
Primary and Secondary Clinical End Points.
Marrouche NF et al. N Engl J Med 2018;378:417-427
Underutilization of CAD Testing among
patients hospitalized with new onset HF• Retrospective cohort study of 67,161 patients with new
onset HF
• Only 17.5% had testing for ischemic CAD during index
hospitalization, increasing to 27.4% at 90 days
• Only 2.1% underwent revascularization during index
hospitalization, increasing to 4.3% at 90 days
• ACC/AHA 2013 guidelines designate Class IIa indication
to noninvasive and invasive assessment of ischemic CAD
in HF patients.
Iron deficiency in heart failure
• 2017 ACC/AHA/HSA guidelines state
• IV iron may be reasonable in selected NYHA functional class II to III
patients with HF (recommendation level II-B)
• 2016 ESC guidelines recommend (II-A) IV iron in
symptomatic HFrEF to alleviate symptoms and imptrove
functional status
Bruno M.L. Rocha et al. JACC 2018;71:782-793
2018 American College of Cardiology Foundation
Sleep disordered breathing
• Most patients with HF have sleep disordered breathing
(SDB) with central (rather than obstructive) sleep apnea
becoming the predominant form in patients with more
severe disease.
• Cyclical apnea and hypopnea are associated with
• Sleep disturbance
• Hypoxemia
• Hemodynamic changes
• Sympathetic activation
• Worse prognosis
• Randomized trials of treatment of central sleep apnea
show possibility of harm
Martin R. Cowie, and Angela M. Gallagher JCHF
2017;5:715-723
2017 American College of Cardiology Foundation
Treatment of central sleep apnea
• Acetazolamide
• Theophylline
• Adaptive servo ventilation
Treatment of central sleep apnea
• Acetazolamide
• Theophylline
• Adaptive servo ventilation
Take home points
• Entresto (sacubitril/valsartan)
• Consider stroke risk for post-MI cardiomyopathy and
normal sinus rhythm
• Catheter ablation for atrial fibrillation and LVEF < 35%
• Test for coronary artery disease in new onset heart failure
HFPEF, PRT 2
Impaired flow pattern and low e’ in male with dyspnea, from Penicka M, Heart, 2014
Stepwise approach to the diagnosis of heart failure with preserved EF in elderly
ambulatory patients with equivocal symptoms. Penicka M, Heart 2014;100: 68-76
Pathophysiology of HFpEF
• Breathlessness is the predominant symptom due to
elevated left ventricular diastolic pressure.
• Focus on abnormalities in active relaxation and passive
stiffness
• Extracellular matrix
• Interstitial fibrosis
• Cardiomyocyte itself
• Incomplete relaxation of myocardial strips
• Increased myocardial stiffness
Pathophysiology of HFpEF
• A new paradigm – Paulus & Tschope – comorbidities such
as obesity, diabetes and COPD lead to a systemic pro-
inflammatory state that induces coronary microvascular
endothelial inflammation.
• This inflammation and resultant oxidative stress cause
stiff myocytes and interstitial fibrosis.
• Although hypertension is commonly felt to cause HFpEF
by afterload excess, this model changes the emphasis to
inflammation
Date of download:
5/14/2014
Copyright © The American College of Cardiology.
All rights reserved.
From: A Novel Paradigm for Heart Failure With Preserved Ejection Fraction: Comorbidities Drive Myocardial
Dysfunction and Remodeling Through Coronary Microvascular Endothelial Inflammation
J Am Coll Cardiol. 2013;62(4):263-271. doi:10.1016/j.jacc.2013.02.092
Myocardial Dysfunction and Remodeling in HFPEF and HFREF
In HFPEF, myocardial dysfunction and remodeling are driven by endothelial inflammation and oxidative stress. In HFREF, oxidative
stress originates in the cardiomyocytes because of ischemia, infection, or toxic agents. ROS trigger cardiomyocyte autophagy,
apoptosis, or necrosis. The latter attracts leukocytes. Dead cardiomyocytes are replaced by fibrous tissue. cGMP = cyclic guanosine
monophosphate; HFREF = heart failure with reduced ejection fraction; other abbreviations as in Figure 1.
Figure Legend:
Pathophysiology of HFpEF
• Vascular abnormalities
• Arterial stiffness increases with aging and is amplified by
hypertension, diabetes and renal disease
• With an increase in arterial stiffness, the ejected pressure
wave is reflected back to the heart, altering systolic
pressure load and diastolic function, increasing hydraulic
work and myocardial oxygen consumption
• This leads to impaired LV reserve function, labile systemic
hypertension, diminished coronary flow reserve and
increased diastolic filling pressures, leading to
breathlessness.
Increased ventriculoarterial stiffness means that older adults have
greater dependence of BP on preload
Pathophysiology of HFpEF
• The end systolic stiffness of the LV and the arteries
increases with aging, especially in women, who are
disproportionately represented in HFpEF
• Women also develop more concentric LVH in the setting
of pressure overload compared to men.
• With exercise, the patient with HFpEF has a limited
vasodilator response to activity.
• These patients often have marked systemic hypertension
with exercise stress.
Treatment of HFpEF
• Pharmacologic management of HFpEF
• Agents in investigational trials
• Sildenafil (RELAX Trial)
• Aldosterone antagonists (TOPCAT Trial)
• Angiotensin-receptor neprilipsin inhibitor ARNI (PARAMOUNT Trial)
• In each case, the information for each trial shows no
benefit of treatment.
More on TOPCAT
Patients Sites Pt/site/mo Mortality
Overall 3,445 233 0.22 4.2-4.6
N & S Am 1,767 188 0.14 6.5-7.7
East. Eur. 1,676 45 0.56 2.0-2.3
Diuretic Treatment in HF
Mechanisms of Loop Diuretic Action and Resistance.
Ellison DH, Felker GM. N Engl J Med 2017;377:1964-1975
Pharmacokinetic and Pharmacodynamic Properties of Loop Diuretics.
Ellison DH, Felker GM. N Engl J Med 2017;377:1964-1975
Nephron Remodeling as a Mechanism of Diuretic Resistance.
Ellison DH, Felker GM. N Engl J Med 2017;377:1964-1975
Causes of Diuretic Resistance.
Ellison DH, Felker GM. N Engl J Med 2017;377:1964-1975
HFPEF PART 3
Stepped-Care Pharmacologic Approach.
Ellison DH, Felker GM. N Engl J Med 2017;377:1964-1975
One more case: BS
• 74 year old female with symptoms of progressive dyspnea and exercise intolerance since February, 2014. No ankle edema.• She tries to exercise on her stationary bike for 10 minutes per day
• PMHx
• Atrial fib, on warfarin, labetalol
• Hypothyroid, on replacement
• Hyperlipidemia
• COPD and restrictive lung disease
• Mitral regurgitation, moderate on 11/25/09
• Exam
• 132/62, HR 58 and irreg.
• Weight 181, Height 5’ 6,” BMI 29.2
• No JVD
• Trace ankle edema
One more case: BS
One more case: BS, Prior study.
One more case: BS
One more case: BS
One more case: BS
One more case: BS, mitral inflow
One more case: BS
Echocardiogram features
• Estimated RVSP (PA systolic pressure) 45 mm Hg
• Septal e’ 7.6 cm/s
• E/e’ 14.7
• Mitral valve deceleration time 201
One more case: BS
• Your diagnosis?
A) Atrial fibrillation with tachycardia cardiomyopathy
B) Diastolic heart failure (HFpEF)
C) Non cardiac dyspnea due to lung disease
D) Deconditioning
E) Labile hypertension
One more case: BS
• You would order
A) CXR
B) BNP
C) Add furosemide, increase until dyspnea resolved
D) Start sildenafil
E) Cardiac rehabilitation exercise, paid by medicare
Exercise and HFpEF
Exercise in HFpEF