Heart failure with preserved ejection fractio

1
Heart Failure with Preserved Ejection
Fraction(HfpEF)ANWER GHANIFIBMSIRAQ
2
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• 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 lt 40), and
• heart failure with mid-range ejection fraction
  (HFmEF, LVEF 40 and lt 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
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• 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.

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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.

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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.
• This process ultimately stimulates cardiomyocyte
  stiffness due to both hypertrophy and titin
  hypophosphorylation, as well as triggering
  myofibroblast activation and interstitial
  fibrosis.

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.

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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.

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Pathophysiology

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

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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.

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Pathophysiology

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

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Pathophysiology

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

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• 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) gt 50
  with normal size of LV (LV end-diastolic volume
  index lt 97 mL/m2), and
• 3- evidence of reduced diastolic LV function.
• (This is usually determined by echocardiography
  (abnormalities of the mitral inflow pattern,
  tissue velocities (e), or the E/e ratio, left
  atrial volume index gt 34 mL/m2, and increased LV
  mass index) or biomarker assessment (NT-proBNP??.)

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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 lt 100 pg/ml,

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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.

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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.

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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.

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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.

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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.

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Prevention

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

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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.

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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.

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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.

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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 ß1-antagonistic action.

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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.

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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.

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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.

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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.

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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.

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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
  .

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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.

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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).

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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.

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Treatment

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

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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.

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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.

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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.

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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.

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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.

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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

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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.

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Treatment

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

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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 BBHas very high B1 selectivity and
  endothelial nitric oxide synthase -stimulating
  and ROS scavenging effects.

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