2. Outline
• Introduction to Diastolic Heart Failure/Heart Failure with Preserved
Ejection Fraction
• Evolving definitions of HFpEF
• Complex Integrated pathophysiologic mechanisms of HFpEF
• Exploring reasons of failed interventions for HFpEF
• Understanding Current management with a clinical case.
• Conclusion
3. Outline
• Introduction to Diastolic Heart Failure/Heart Failure with Preserved
Ejection Fraction
• Evolving definitions of HFpEF
• Complex Integrated pathophysiologic mechanisms of HFpEF
• Exploring reasons of failed interventions for HFpEF
• Understanding Current management with a clinical case.
• Conclusion
4. HFpEF-A Road less travelled
1980s
HF exclusively Systolic
dysfunction
RCTs included only
reduced EF
patients
Subsequent data on
Normal EF HF
(Diastolic HF)
HFrEF <40%
HFpEF >50%
HFmrEF 40-49%
Half of total HF cases have HFpEF
No Proven therapy that has shown reduction in
Morbidity & Mortality for HFpEF
6. What is HFpEF?
• Challenges associated with HFpEF begin with its definition
• The definition of HFpEF has evolved over the last 2 decades
• Moving from echocardiographic evidence of diastolic dysfunction in
the setting of an EF>50%, towards a definition including cardiac
structural abnormalities resulting from
• high filling pressures,
• diastolic abnormalities,
• elevated biomarkers,
• elevated left heart filling pressures by invasive hemodynamic assessment
7. Outline
• Introduction to Diastolic Heart Failure/Heart Failure with Preserved
Ejection Fraction
• Evolving definitions of HFpEF
• Complex Integrated pathophysiologic mechanisms of HFpEF
• Exploring reasons of failed interventions for HFpEF
• Understanding Current management with a clinical case.
• Conclusion
9. Outline
• Introduction to Diastolic Heart Failure/Heart Failure with Preserved
Ejection Fraction
• Evolving definitions of HFpEF
• Complex Integrated pathophysiologic mechanisms of HFpEF
• Exploring reasons of failed interventions for HFpEF
• Understanding Current management with a clinical case.
• Conclusion
10. Risk Factors
Age is a risk factor for HF, and the incidence of HFpEF increases more dramatically with age
than the incidence of HFrEF
When other HFpEF risk factors (age, obesity, blood pressure, current treatment for hypertension, and
previous myocardial infarction) are adjusted for, women are not at a higher risk of HFpEF than men
Exposure to ionizing radiation therapy—even at the low cardiac doses resulting from contemporary breast
cancer radiotherapy—has been shown to increase the risk of HFpEF
11. HEpEF- A Single disease entity or many
different diseases?
Limitations
in systolic
reserve
changes in
body
compositio
n
chronotropic
incompetenc
e
left atrial
function
vascular
function
skeletal
muscle
function
Age
associated
changes
Single disease Entity
Multiple disease Entity
nitric oxide
bioavailability
12. Outline
• Introduction to Diastolic Heart Failure/Heart Failure with Preserved
Ejection Fraction
• Evolving definitions of HFpEF
• Complex Integrated pathophysiologic mechanisms of HFpEF
• Exploring reasons of failed interventions for HFpEF
• Understanding Current management with a clinical case.
• Conclusion
13. Promising interventions failed to demonstrate a
definitive benefit in HFpEF patients ?
Failed trial designs or Inefficacious study interventions ?
14. Morphological and functional heterogeneity in
HFpEF Clinical Trials
Should the interventions be studied in a broad group of subjects or in
small group subjects focusing on individual subpopulations ?
15. • To date, HFpEF clinical trials have also adopted broad inclusion
criteria.
• Ensuring adequate statistical power to detect signals may be
especially important in HFpEF trials, given the many comorbid
conditions in HFpEF, which may influence clinical endpoints beyond
HF severity and therapeutic effect.
• The right patients need to be matched to the therapies from which
they are most likely to benefit
16. Ongoing set of studies target unique mechanistic
hypotheses but not specific subphenotypes
17. Subpopulation: at-risk/metabolic disorders-
Impact of preventive interventions in HFpEF vs HFrEF
• Prevention, or delay in progression, of HFpEF may be effective in high-
risk populations
SGLT-2 inhibitors
showing reduced
HF incidence in
Type 2 DM with
CVD
18. Subpopulation: elevated left atrial pressure
However, there's a sizable base of evidence that inorganic nitrate or nitrite administration promote
favorable nitric oxide (NO) effects on vascular function
The only subgroups to show signs of a positive effect from nitrite intake were those who entered the study
with higher levels of brain-type natriuretic peptide (BNP) and the nearly half of the cohort who were in atrial
fibrillation (AF)
Further studies using a variety of inorganic nitrite/nitrate formulations are ongoing
20. Outline
• Introduction to Diastolic Heart Failure/Heart Failure with Preserved
Ejection Fraction
• Evolving definitions of HFpEF
• Complex Integrated pathophysiologic mechanisms of HFpEF
• Exploring reasons of failed interventions for HFpEF
• Understanding Current management with a clinical case.
• Conclusion
21. Clinical Case Vignette
• A 73-year-old woman with a history of dyspnea on exertion presents for a follow-up visit
after hospitalization for acute worsening of dyspnea and orthopnea.
• On admission to the hospital, the patient had atrial fibrillation with a ventricular rate of
120 beats per minute,
• CXR= pulmonary venous hypertension.
• Continues to have fatigue and exertional dyspnea, despite anticoagulation, rate control
with a beta-blocker, and administration of loop diuretics during the hospitalization,.
• BMI is 39, PR=76 bpm, and BP160/70 mm Hg.
• JVP distention and lower-extremity edema but no third heart sound, murmurs, or rales.
S.creatinine=1.4 mg/dl, eGFR=37 ml per minute per 1.73 m2 of body-surface area, and NT-
proBNP level 300 pg/ml.
• Echocardiography reveals an EF=70%, a normal left ventricular cavity dimension and wall
thickness, and left atrial enlargement. Doppler echocardiography shows elevated left atrial
pressure (E/e′ ratio, 22) and an estimated pulmonary-artery systolic pressure of 52 mm Hg.
25. Evidence of a reduction in HF hospitalisation, however these were secondary end points
Both angiotensin II receptor blockers and aldosterone receptor antagonists have a class IIb
indication to reduce the risk of HF hospitalisation
27. Clinical Case Vignette
• The dose of diuretics should be increased to reduce the patient’s clinical
congestion.
• For hypertension and renal dysfunction, an ARB should be added and other
agents used as needed to achieve a blood pressure of less than 140/90 mm Hg.
• Educate regarding self-care for heart failure.
• Anticoagulation should be continued. If symptoms persist, a trial of rhythm
control should be considered.
• The patient’s atherosclerotic risk and the presence of coronary disease should be
assessed to guide the use of statins and other treatments for coronary disease.
• Evaluation for sleep apnea may also be reasonable, given her obesity, fatigue,
hypertension, and atrial fibrillation.
• Once stable, exercise and weight-loss programs should be commenced.
28. Outline
• Introduction to Diastolic Heart Failure/Heart Failure with Preserved
Ejection Fraction
• Evolving definitions of HFpEF
• Complex Integrated pathophysiologic mechanisms of HFpEF
• Exploring reasons of failed interventions for HFpEF
• Understanding Current management with a clinical case.
• Conclusion
29. Conclusion
• Given the challenges in the diagnosis of HFpEF, systematic study of
diagnostic techniques and strategies to enhance recognition of HFpEF
are needed.
• The evidence base for existing pathophysiologic paradigms is not
mature. Thus, there is an urgent need for integrated human studies
elucidating the underlying pathophysiology leading to HFpEF and
development of corresponding clinically relevant animal models.
• Promising agents should be targeted for carefully designed phase II
studies using surrogate endpoints
31. Subpopulation: Pulmonary Vascular Disease
Many HFpEF
patients have PH,
which is
associated with
increased
symptom burden,
hospitalizations,
and mortality and
unique histo-
pathology
an underlying proinflammatory state (caused by 1 or more of the commonly associated comorbid conditions in HFpEF, including obesity, diabetes, and hypertension) triggers a cascade of events that leads to decreased nitric oxide bioavailability, cyclic guanosine monophosphate, and protein kinase G activity, thereby causing increased cardiomyo- cyte stiffness (due to titin hypophosphorylation) and/or interstitial myocardial fibrosis, and increased ventricular wall stiffness
he prevalence of left ventricular hypertrophy (A), left atrial dilation (B), and diastolic dysfunction (C) is highly variable, as demonstrated in major randomized heart failure with preserved ejection fraction (HFpEF) trials (I-PRESERVE [Irbesartan in Heart Failure With Preserved Ejection Fraction], CHARM [Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity]-Preserve, and TOPCAT [Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial]). LA 1⁄4 left atrial; LVH 1⁄4 left ventricular hypertrophy.
Heart failure (HF) hospitalisation across 6 major phase 3 trials of pharmacologic therapy in heart failure with preserved ejection fraction (HFPEF). I-PRESERVE indicates irbesartan in patients with heart failure and preserved systolic function; PEP-CHF indicates Perindopril in Elderly People with Chronic Heart Failure; TOPCAT, Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist; CHARM-P, Candesartan in heart failure - assessment of moRtality and Morbidity - preserved; DIG-Ancillary, digitalis investigation group trial - ancillary study; J-DHF, Japanese diastolic heart failure study
PH-HFpEF, features, and treatment options. The middle photo-inlet shows histological features of pulmonary vascular remodelling including
(A) mild medial hypertrophy of a pulmonary artery, (B) haemangiomatosis-like endothelial cell proliferation of pulmonary capillaries, and (C) pulmonary venous remodelling. The cardiac magnetic resonance images show signs of HFpEF (LV hypertrophy, LA dilatation) without (left inlet) and with (right inlet) signs of PH
Ejection fraction values of 40 to 49% are considered to be a gray area but are probably consistent with heart failure
and a preserved ejection fraction in some patients. Common alternative or contributing conditions that should be considered are cardiac ischemia due to epicardial coronary disease, lung disease, or pulmonary arterial hyperten- sion that is unrelated to heart failure. Hypertrophic or infiltrative cardiomyopathy, pericardial disease, or uncorrect- ed primary valve disease should be ruled out. In the outpatient setting, heart failure is less likely in patients with a brain natriuretic peptide (BNP) level of less than 35 pg per milliliter or an N-terminal pro–brain natriuretic peptide (NT-proBNP) level of less than 125 pg per milliliter than in patients with higher levels.17 However, patients who have heart failure with a preserved ejection fraction can have normal natriuretic peptide levels, particularly if they are obese or have only exertional symptoms. E/A denotes ratio of E wave to A wave, E/e′ ratio of early mitral inflow ve- locity (E) to early diastolic mitral annular velocity detected by tissue Doppler imaging (e′).