Heart failure with preserved ejection fraction

1. Heart Failure with Preserved Ejection Fraction
(HfpEF)
ANWER GHANI
FIBMS
IRAQ

2. .
Heart failure (HF) is divided into three forms based on left
ventricular (LV) ejection fraction (LVEF):
heart failure with preserved ejection fraction (HFpEF, LVEF ≥ 50%),
heart failure with reduced ejection fraction (HFrEF, LVEF < 40%), and
heart failure with mid-range ejection fraction (HFmEF, LVEF ≥ 40 and < 50%).

3. .
 Fifty per cent (50%) of HF patients are in the
subset of heart failure with preserved ejection
fraction (HFpEF) whose 3 year mortality
prognosis approximates to 50%.

4. .
HFpEF has a global prevalence of 2%

5. .
Compared with the rapid development in the treatment of heart
failure with reduced ejection fraction, HFpEF presents a great
challenge and needs to be addressed considering the failure of HF
drugs to improve its outcomes.

6. Clinical Features
Patients suffering from HFpEF are older, mostly female and obese,
and exhibit a lower prevalence of coronary artery disease (CAD)
than patients with HFrEF.

7. Clinical Features
Patients with AF and underlying HFpEF have reduced exercise
tolerance and worsened ventricular function than those with AF
alone.

8. Clinical Features
HFpEF is a systemic syndrome involving multiple organs. Diastolic
factors affecting HFpEF are the pulmonary vein (preload), vascular
resistance (afterload), and contractility relaxation (cardiac).

9. Clinical Features
HFpEF is triggered by the cumulative expression of various risk
factors and comorbidities, including
age, sex (female), physical inactivity, obesity,
AF, CAD, Hypertension,
diabetes, dyslipidemia, metabolic syndrome,
chronic kidney disease, anemia,
chronic obstructive pulmonary disease and sleep-disordered
breathing.

10. Pathophysiology
HFpEF is associated with endothelial inflammation, leading to
coronary microvascular dysfunction.
Endothelial dysfunction is a significant factor linking cardiac and
extracardiac effectors.

11. Pathophysiology
The changed composition and structure of both cardiomyocytes
and noncardiomyocytes can increase diastolic stiffness and
promote HFpEF development.

12. Pathophysiology
 A recent hypothesis regarding pathophysiology
in HFpEF suggests that coronary microvascular
inflammation, rather than afterload mismatch, is
the primary driver of fibrosis and cardiomyocyte
hypertrophy.
 Co‐morbidities such as obesity and ageing
contribute to a chronic systemic
proinflammatory state, resulting in coronary
microvascular inflammation, NO dysregulation
and oxidative stress.

13. Pathophysiology
Both obesity and diabetes are accompanied by increased epicardial
adipose tissue volume, which transduces the effects of these
diseases on cardiac function and structure.
Both obesity and diabetes lead to an inflammatory and fibrotic
atrial and ventricular myopathy, the two major elements of HFpEF.

14. Pathophysiology
Obesity and diabetes increase the risk of exercise intolerance and
promote rapid progression of HFpEF due to multimorbidity,
impaired chronotropic reserve, left ventricular hypertrophy, and
activation of inflammatory, pro-oxidative, vasoconstrictor, and
profibrotic pathways.

15. Pathophysiology
Although LVEF is not reduced, increased LV-filling pressure results in
exertional dyspnea and exercise intolerance.

16. Pathophysiology
AF may be the first indicator of an inflammatory or metabolic LA
myopathy causing HFpEF
AF reflects the development of myocardial inflammation, fibrosis,
and hypertrophy in parallel with atrial and ventricular myopathy
that results in HFpEF.

17. Pathophysiology
Cardiometabolic abnormalities, such as abnormal mitochondrial
function, changed substrate utilization, and intracellular calcium
overload, are also considered pathophysiological mechanisms in
HFpEF.

18. Pathophysiology
Aging promotes coronary microvascular endothelial abnormalities
and myocardial remodeling and dysfunction in HFpEF.

19.  European Society of Cardiology and American
Heart Association: three criteria for the
diagnosis of HFPEF:
 1-clinical signs and/or symptoms of HF,
 2- normal or mild reduction of systolic with left
ventricular (LV) ejection fraction (LVEF) > 50%
with normal size of LV (LV end-diastolic volume
index < 97 mL/m2), and
 3- evidence of reduced diastolic LV function.
(This is usually determined by echocardiography (abnormalities of the mitral inflow pattern, tissue

20. Diagnosis
Patients with increased LV-filling pressures related to HFpEF
commonly have no elevated BNP levels, possibly because
distensibility is impaired by myocardial fibrosis or due to coexistent
obesity.
Most studies have suggested that around 30% of HFpEF patients
have a BNP < 100 pg/ml,

21. Diagnosis
The limited ability of echocardiographic variables in identifying
diastolic dysfunction further challenges its diagnosis in clinical
practice.

22. Diagnosis
Cardiac magnetic resonance imaging provides structural evidence
of HFpEF, such as increased epicardial adipose tissue volume and
myocardial fibrosis.

23. Diagnosis
Cardiac catheterization is the best method to confirm increased LV-
filling pressure.

24. Prevention
Hypertension can obviously increase prevalence, rehospitalization
and mortality of patients with HFpEF; thus, treating hypertension
may be the most effective prevention method for HFpEF.

25. Prevention
CAD deteriorates ventricular function and outcomes and increases
the occurrence of HFpEF, and patients with CAD patients should
receive systemic treatment, such as coronary revascularization.

26. Prevention
Tachycardia is also deleterious by shortening diastole time and
impairing diastolic filling. Rate or rhythm control of AF may prevent
the development of an underlying HFpEF.

27. Prevention
Anemia is related to elevated prevalence, hospitalization and
mortality of HFpEF.

28. Prevention
Enhancing mitochondrial energy by iron supplementation prevents
the development of HFpEF, and iron supplementation rather than
erythropoietin is recommended.

29. Prevention
Lifestyle modifications, such as dietary control, nutrient
management, physical activity, weight loss, and cardiorespiratory
fitness, have beneficial effects on the prevention of HFpEF.

30. Prevention
Treating obesity or diabetes can affect the volume or function of
epicardial adipose tissue.

31. Prevention
Both caloric restriction and physical activity are effective methods
to improve cardiac outcomes in patients with HFpEF.

32. Prevention
Weight loss reduces the risk of HFpEF, lowers elevated diastolic
filling pressure, and alleviates epicardial adipose inflammation.

33. Treatment
Angiotensin-converting enzyme inhibitors and angiotensin receptor
blockers (ARBs) can alleviate the inflammation of adipose and
attenuate myocardial fibrosis and remodeling. They improve clinical
symptoms and exercise tolerance rather than morbidity or
mortality in patients with HFpEF.

34. Treatment
Aldosterone mediates myocardial fibrosis, contributing to
myocardial stiffness
Mineralocorticoid receptor antagonists fail to improve clinical
symptoms, exercise tolerance, and cardiac outcomes in patients
with HFpEF.

35. Treatment
Beta-blockers have no prognostic effect in patients with HFpEF .
Nebivolol is expetion, it has benefit, may be due to vasodilatory
effect due to nitric oxide-releasing properties.The endothelial nitric
oxide synthase -stimulating and ROS scavenging effects of nebivolol
act synergistically to provide cardiovascular protection in addition
to its β1-antagonistic action.

36. Treatment
Beta3-adrenoreceptor prevents neurohormonal stimulation and
myocardial hypertrophy . Stimulating Beta3-adrenoreceptor with
selective agonist mirabegron may be studied as a treatment
method in HfpEF.

37. Treatment
Cardiac glycosides, such as digoxin, cannot improve cardiac
mortality but treat the tachyarrhythmia in HFpEF . However,
atrioventricular node blocking drugs, such as digoxin, can exert
lethal proarrhythmic effects independent of slowing heart rate.

38. Treatment
Statins can decrease epicardial adipose tissue volume and thereby
prevent systemic inflammation and myocardium fibrosis. Statins
reduce new-onset and recurrent AF and further prevent AF-related
thromboembolic events.
Meanwhile, the application of Lipophilic statins; atorvastatin is
followed by improved diastolic dysfunction and reduced HFpEF risk.

39. Treatment
Natriuretic peptides activate guanylyl cyclase, resulting in cyclic
guanosine monophosphate (cGMP) formation and preventing
myocardial fibrosis due to vasodilation and diuresis . The addition
of neprilysin inhibition to ARBs [sacubitril/valsartan; angiotensin
receptor-neprilysin inhibitor (ARNI)] ameliorates atrial and
ventricular myopathy in patients with HfpEF.
There is evidence from a meta-analysis that sacubitril/valsartan in
HFpEF probably reduces HFpEF hospitalization but probably has
little or no effect on cardiovascular mortality and life quality.

40. Treatment
Direct nitric oxide (NO) donators, including organic nitrates
(isosorbide-nitrate), are not recommended in patients with HFpEF,
considering their disadvantages of vasodilatation and hypotension.
They also fail to increase exercise tolerance and improve diastolic
function.

41. Treatment
Soluble guanylyl cyclase (sGC) activators, such as vericiguat and
riociguat, are administered in patients with Pul.AH. Vericiguat has
recently been demonstrated to reduce cardiac mortality in patients
with HFrEF.

42. Treatment
Metformin reduces proinflammatory adipokines and has anti-
inflammatory roles. It reduces the risk of AF and improves diastolic
dysfunction in HFpEF .

43. Treatment
Pioglitazone and rosiglitazone suppress atrial and ventricular
inflammation and fibrosis and reduce the risk of AF and HfpEF
Thiazolidinediones have been associated with an improved diastolic
filling abnormality in patients with diabetes. However, they
promote sodium retention, thereby increasing cardiac volume.
Sodium retention may aggravate cardiac fibrosis and hypertrophy
and increases the risk of HFpEF.

44. Treatment
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as
dapagliflozin and empagliflozin, achieve significantly decreased
primary composite endpoint of worsened HF or cardiac mortality in
patients with HFrEF, which is independent of diabetes. SGLT2
inhibitors reduce the volume of epicardial adipose and cardiac
events caused by HfpEF.
Symptoms of heart failure with preserved ejection fraction (HFpEF)
improved with dapagliflozin (Forxiga).

45. Treatment
The results of existing evidence do not support the use of
glucagonlike peptide-1 (GLP-1) agonists like liraglutide or
semaglutide in HF with diabetes, and LIVE points out the potential
harmful effect of liraglutide in this population.

46. Treatment
As an anti-fibrotic drug, pirfenidone suppresses the development of
ventricular fibrosis and diastolic dysfunction through targeting
transforming growth factor β (TGF-β) signaling pathway in
pressure-overload induced HF.

47. Treatment
Lysyl oxidase-like 2 (Loxl2) promotes collagen's cross-linking and
causes interstitial fibrosis.
Diastolic function may be improved by antibody-mediated
inhibition of Loxl2 . (PXS-5382) Inhibits of Loxl2 and new cross-
linking strategies will be assessed in the future.

48. Treatment
Systemic inflammation is the main mediator in HFpEF, and cytokine
inhibitors have been considered therapeutic options.
Although interleukin-1 (IL-1) blockade with anakinra cannot
improve exercise tolerance, canakinumab, a monoclonal antibody
targeting IL-1ß, decreases HF hospitalization and mortality.

49. Treatment
Cardiolipin is a significant phospholipid in the inner mitochondrial
membrane, and Szeto-Schiller (SS) peptide is an antioxidant peptide
binding to cardiolipin.
Elamipretide reduces LVEDP in patients with HFpEF.

50. Treatment
Neladenoson bialanate, a partial adenosine A1 receptor agonist,
may benefit both cardiac and skeletal muscles. It enhances
SERCA2a activity and reverses ventricular remodeling through
improving mitochondrial function but fails to significantly affect
exercise tolerance in patients with HFpEF.

51. Treatment
Levosimendan has positive inotropic and vasodilative effects
through a combined effect on calcium sensitization and
phosphodiesterase-3 inhibition.
It improves inflammatory process and diastolic function in patients
with HFrEF.

52. Treatment
Ivabradine (Corlanor), a drug that inhibits the I f channel in sinus node, has
been found to improve LV systolic and diastolic function in an angiotensin II-
induced HF mouse.
In patients with HFpEF, HR reduction with ivabradine did not improve outcomes.
These findings do not support the use of ivabradine in HFpEF.

53. Treatment
 Serelaxin, recombinant human relaxin might play a role in potential
benefits in patients with HFPEF due to additional properties including
antifibrosis, anti-inflammatory, and anti-ischemic.
 RELAX‐AHF‐1 suggested that the serelaxin‐mediated clinical
responses and favourable changes in HF‐relevant biomarkers of
organ damage were similar in the HFpEF subgroup compared with
that observed in patients with reduced ejection fraction.
 A recent hypothesis regarding pathophysiology in HFpEF suggests that coronary microvascular
inflammation, rather than afterload mismatch, is the primary driver of fibrosis and cardiomyocyte
hypertrophy

54. Treatment
 As an antianginal agent and late sodium channel inhibitor,
ranolazine might improve LV diastolic function through
inhibition of late sodium current or probably a direct effect on
myofilament cross-bridge kinetics and myofilament sensitivity to
calcium.
 Ranolazine improved measures of hemodynamics but that there
was no improvement in relaxation parameters.

55. Treatment
Meanwhile, inhaled iloprost causes an acute reduction of PAP in
patients with HFpEF .
Diuretics are established drugs to treat fluid overload.

56. Treatment of HFpEF
-Sacubitril/valsartan (Entresto) 24 mg/26 mg. angiotensin receptor neprilysin inhibitor
(ARNI).
-Empaglifozin (Jardiance) 10 mg, Dapaglifozin (Forxiga) 10 mg: sodium-glucose co-
transporter 2SGLT-2 inhibitor
-Elamipretide (Bendavia) 40 mg: mitochondrion-targeted antioxidant
-Pirfenidone (Pirfenex)) 267 mg: inhibit collagen synthesis.
-Vericiguat (Verquva) 5 mg, Riociguat (Adempas) 1 mg: a stimulator of soluble
guanylate cyclase sGC
-Levosimendan ( Simendan) 12.5 mg inj: Ca2+ sensitizing inotropic agent
-Atorvustatin (Lipitor) 20 mg: Lipophilic statins; muscle sympathetic nerve activity
(MSNA) inhibitors. (Hydrophelic statins are not effectice)
-Canakinumab (Ilaris) 150 mg sc , a monoclonal antibody targeting IL-1ß, anti-
inflammatory. Dose related.
-Serelaxin (Reasanz)1mg/ml : Recombinant human relaxin; has anti-fibrotic effects.
-Metformin (Glucophage) 500 mg: lowering titin-based passive stiffness.
-Nebivolol ( Bystolic ): Nebivolol is a 3rd generation BB;Has very high B1 selectivity and
endothelial nitric oxide synthase -stimulating and ROS scavenging effects.

57. ‘‘
‘‘
.
THANKS