HF With Preserved EF

Because some of these patients do not have entirely normal EF but also do not have major reduction in systolic
function, the term preserved EF has been used.

The criteria that define the syndrome of HFpEF include:

a) clinical signs or symptoms of HF;
b) evidence of preserved or normal LVEF; and
c) evidence of abnormal LV diastolic dysfunction that can be determined by Doppler echocardiography or
cardiac catheterization.

Patients with HFpEF are usually older women with a history of hypertension. Obesity, CAD, diabetes mellitus,
atrial fibrillation (AF), and hyperlipidemia are also highly prevalent in HFpEF. Hypertension remains the most
important cause of HFpEF, with a prevalence of 60% to 89% from large controlled trials.
Pathophysiology of HFpEF
 Pathophysiology of HFpEF
A] HF is explained by diastolic LV dysfunction, which consisted of:
1. prolonged isovolumic LV relaxation,
2. slow LV filling, and
3. increased diastolic LV stiffness.

B] Other mechanisms include:

1. resting and exercise-exacerbated systolic dysfunction,
2. impaired ventricularvascular coupling,
3. Vascular dysfunction: abnormal exercise-induced and flow mediated vasodilation,
4. chronotropic incompetence, and
5. Systolic and diastolic Cardiovascular Reserve Dysfunction.
 A] Diastolic Left Ventricular Dysfunction
In the absence of endocardial or pericardial disease,
diastolic LV dysfunction results from:
increased myocardial stiffness.
Determinants of myocardium stiffness are:
1. the extracellular matrix and
2. the cardiomyocytes.
3. matricellular proteins.

1. Stiffness of the extracellular matrix: is largely determined by excessive collagen type I deposition due to exaggerated
synthesis and a depressed degradation. The depressed degradation is due to downregulation of matrix metalloproteinases
(MMPs) and upregulation of tissue inhibitors of matrix metalloproteinases .
2. Intrinsic cardiomyocyte stiffness is related to the cytoskeletal protein titin [a giant elastic protein expressed in
cardiomyocytes].
3. Matricellular Proteins: A stiffness change is transmitted from one compartment to the other compartment via
matricellular proteins.
By binding to collagen, cell surface receptors, and MMPs, matricellular proteins improve both matrix quality and
cardiomyocyte function. Their role in HFpEF remains unexplored.
 B.1] Systolic dysfunction
Ejection fraction is preserved in HFpEF, but EF is more accurately regarded as a measure of ventriculararterial
coupling than contractility alone.

Systolic functions , assessed by Tissue Doppler imaging, are impaired (longitudinal and radial systolic function) in
HFpEF, despite a normal global measures of systolic function (Normal EF).

The extent of myocardial contractile dysfunction in HFpEF was associated with increased mortality, suggesting that
it may be a mediator or nominally a marker of more severe disease.

End-systolic elastance (Ees), defined by the slope and intercept of the end-systolic pressurevolume relationship, is
a gold standard measure of chamber contractility that, in contrast to other measures, is elevated in HFpEF despite
depressed contractility.

Ees is also influenced by chamber geometrybeing increased with concentric remodelling and passive ventricular
stiffeningprocesses commonly observed in HFpEF.

It is speculated that the same processes that promote diastolic ventricular stiffening in HFpEF also increase systolic
stiffening (Ees) and contribute to reduced myocardial contractility and limited systolic reserve.
 B.2] Ventricular-arterial Coupling: Ees/Ea
Ventricular and vascular stiffening increase with ageing, hypertension,
and diabetes, and are abnormally elevated in patients with HFpEF.

Both arterial elastance (Ea) and End-systolic elastance (Ees) are elevated in HFpEF,
explaining the labile blood pressure swings commonly seen in HFpEF. Combined
ventricular-arterial stiffening leads to greater blood pressure lability.

Systemic vasorelaxation with exercise is attenuated in HFpEF, promoting

impaired delivery of blood flow to skeletal muscle.

B.3] Vascular Dysfunction

Vascular dysfunction in HFpEF may be due in part to endothelial dysfunction

[abnormal exercise-induced and flow-mediated vasodilation (a biomarker of
endothelial function)] .

Vascular dysfunction is not confined to the systemic circulation in HFpEF, as pulmonary

hypertension is frequently observed as well.
Arterial elastance EA = ESP / SV (SV stroke volume) Higher
elastance = greater sensitivity to volume change, more variable
pressure

Ventricular elastance (Ees) ELV = ESP / ESV (ESV LV end-systolic

volume) Net arterial load exerted on the ventricle

VAC = EA / ELV
= ESP / SV ESP / ESV
= ESP / SV 1 / (ESP / ESV)
= ESP / SV ESV / ESP
= ESV/SV

SV = VTI x CSA
 B.4] Chronotropic Incompetence
During physical exertion in normal subjects , cardiac output increases through integrated enhancements in venous return,
contractility, heart rate, and peripheral vasodilation.

Chronotropic reserve is depressed in HFpEF, independent of rate-slowing medication use. This is likely related to
downstream deficits in -adrenergic stimulation.

B.5] Systolic and diastolic Cardiovascular Reserve Dysfunction

B.5.1] Diastolic Cardiovascular Reserve Dysfunction: Diastolic reserve is also reduced with exertion in HFpEF, Just as
impairment of diastolic function [patients display blunted increases in preload volume with exercise, despite marked
elevations in filling pressure]. This is likely related to increased chamber stiffness and inadequate enhancement of
early relaxation.

B.5.2] Systolic Cardiovascular Reserve Dysfunction: Systolic reserve with exertion is also impaired in HFpEF [patients
display blunted increases in EF, contractility, and longitudinal systolic shortening velocities during exercise].
Exercise stress may 'unmask' mild deficits in resting systolic function, and the inability to reduce end-systolic volume,
combined with less increase in end-diastolic volume, greatly limits stroke volume responses during exercise.

The causes of systolic and diastolic reserve dysfunction in HFpEF remain unclear, but may be related to myocardial
ischaemia (epicardial/microvascular coronary disease or vascular rarefaction), impaired -adrenergic signalling,
myocardial energetics, or abnormal calcium handling.
Diagnosis of HFpEF
Four sets of guidelines for the diagnosis of HFpEF
They all require the simultaneous and obligatory presence of signs and/or symptoms of HF, evidence of normal
or only mildly abnormal LV systolic function, and evidence of diastolic LV dysfunction or of surrogate markers of
diastolic LV dysfunction (such as a) LV hypertrophy, b) LA enlargement, c) atrial fibrillation, or d) elevated plasma
natriuretic peptides (NP) levels).

1] The first set of guidelines was provided by the **WG on Myocardial Function of the ESC /1998: 1] Signs or
symptoms of CHF include evidence of raised LAP, such as exercise intolerance, exertional dyspnoea, orthopnoea,
gallop sounds, lung crepitations and pulmonary oedema. 2] Presence of normal or mildly reduced LV systolic
function [LVEF45% and normal LVEDIDI<32 cm/M2 or normal LVEDVI<102 ml/m2]. 3] Evidence of diastolic LV
dysfunction as slow isovolumic LV relaxation, slow early LV lling, reduced LV diastolic distensibility and increased
LV chamber diastolic stiness.

2] The second set of guidelines was provided by the (National Heart, Lung, and Blood Institute) NHLBI
**Framingham Heart Study (Circulation 2000) and combined 1] signs and symptoms of HF, 2] normal LVEF (>50%),
and 3] invasive evidence of diastolic LV dysfunction.

3] The third set of guidelines implement their assessment with a scoring system of major and minor criteria and
use LV hypertrophy and LA enlargement as surrogate markers of diastolic LV dysfunction. **[Prog Cardiovasc Dis
2005;47:314319].

4] The last set of guidelines was provided by the Heart Failure and Echocardiography Associations of the European
Society of Cardiology **[Eur Heart J 2007;28:25392550].
Treatment
ACCF/AHA Stages of HF NYHA Functional Classification
At high risk for HF but without
A structural heart disease or symptoms of None
HF
Structural heart disease but without No limitation of physical activity. Ordinary physical
B I
signs or symptoms of HF activity does not cause symptoms of HF.
No limitation of physical activity. Ordinary physical
I
activity does not cause symptoms of HF.
Slight limitation of physical activity. Comfortable at
II rest, but ordinary physical activity results in
Structural heart disease with prior or symptoms of HF.
C
current symptoms of HF Marked limitation of physical activity. Comfortable
III at rest, but less than ordinary activity causes
symptoms of HF.
Unable to carry on any physical activity without
IV
symptoms of HF, or symptoms of HF at rest.
Refractory HF requiring specialized Unable to carry on any physical activity without
D IV
interventions symptoms of HF, or symptoms of HF at rest.
 A] Important Risk Factors for HF
1] Hypertension: may be the single most important modifiable risk factor for HF.

2] Diabetes Mellitus: It markedly increases the likelihood of developing HF in patients without structural heart
disease and adversely affects the outcomes of patients with established HF.

3] Metabolic Syndrome: includes any 3 of the following: abdominal adiposity, hypertriglyceridemia, low high-density
lipoprotein, hypertension, and fasting hyperglycaemia.

4] Atherosclerotic Disease: (e.g., of the coronary, cerebral, or peripheral blood vessels).

 Treatment of Stages A to D
Stage A: Recommendations
Class I
1. Hypertension and lipid disorders should be controlled in accordance with contemporary guidelines to lower the
risk of HF. (Level of Evidence: A)
2. Other conditions that may lead to or contribute to HF, such as obesity, diabetes mellitus, tobacco use, and
known cardiotoxic agents, should be controlled or avoided. (Level of Evidence: C)
Stage B: Recommendations

Stage B: Recommendations

Clyde W. Yancy et al. Circulation. 2013;128:e240-e327

 Pharmacological Treatment for Stage C HFpEF:
Recommendations
Class I:
Systolic and diastolic blood pressure should be controlled in patients with HFpEF in accordance with published
clinical practice guidelines to prevent morbidity. (Level of Evidence: B)
Diuretics should be used for relief of symptoms due to volume overload in patients with HFpEF. (Level of Evidence: C)

Class IIa
Coronary revascularization is reasonable in patients with CAD in whom symptoms (angina) or demonstrable myocardial
ischemia is judged to be having an adverse effect on symptomatic HFpEF. (Level of Evidence: C)
Management of AF according to published clinical practice guidelines in patients with HFpEF is reasonable to improve
symptomatic HF. (Level of Evidence: C)
The use of beta-blocking agents, ACE inhibitors, and ARBs in patients with hypertension is reasonable to control blood
pressure in patients with HFpEF. (Level of Evidence: C)