Senior Talk GilbertRoy Kamoga

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Senior TalkGilbert-Roy Kamoga
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Case 65 y/o lady presents to the ED with acute
onset shortness of breath started 6 hours ago.
She has history of DM, HTN, DLD. Just prior to
this episode she felt like her heart was racing.
She is axnious. She denies any previous dyspnea
on exertion, lower extremity swelling or
abdominal distension. She had been feeling well
the day prior. In ED her vitals were 36.5 125
192/100 27 83 on RA. She was in Resp distress,
sweaty seated upright. S1, S2 and S4 heard,
irregular with no m/g/r and no JVD. She had fine
crackles 2/3 up her lung fields posteriorly.
Abdomen unremarkable. No peripheral edema,
peripheral pulses palpable. Whats the diagnosis?
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Heart Failure with Preserved Ejection
Fraction(HFPEF)
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Objectives

• 1. Definition of HFPEF
• 2. Describe the Epidemiology
• 3. Elaborate on Pathophysiology
• 4. Clinical Features and Diagnosis
• 5. Management Strategies
• 6. Take home Message

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Definition

• The diagnosis of Heart failure with Preserved
  Ejection Fraction is based on the clinical
  finding of congestive heart failure with the
  echocardiography findings of preserved left
  ventricular ejection fraction and the absence of
  valvular abnormalities.
• (ACC/AHA guidelines)

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Epidemiology
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Population based prevalence studies suggest that
nearly half the patients with heart failure have
HFPEFThe proportion of the patients with HFPEF
in the various studies ranges from 40-71 (mean
56). These prevalence studies are compromised by
the precise threshold for what is considered to
be a normal Left Ventricular Ejection
Fraction.One study elaborated that 80 of heart
failure patients had an LVEF gt 0.45 but only 55
had an LVEF gt 0.55
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In hospital-based cohort studies the proportion
of patients with HFPEF is slightly lower, ranging
from 24-55 (mean 41) Possible explanation for
this observation is that patients with HFPEF have
less severe symptoms and / or are less frequently
hospitalized. Among patients hospitalized for
ADHF worldwide data suggest that about 1/3 will
have normal LVEF in the West compared to Asia
and India where 50 will have normal EF. This is
thought to be due to the high prevalence of
poorly treated hypertension.
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The mortality of diastolic heart failure (HFPEF)
ranges between 5-8 per year, which is about half
of that for systolic heart failure. The
morbidity, hospitalization rates and healthcare
costs per patient are very similar between
patients with HEPEF and those with SHF. The
Framingham Heart study reported annual mortality
of 8.7 for HFPEF compared with 3 in matched
controls and for SHF was 18.9 compared with a
4.1 in age- and sex- matched controls over 6.2
years.
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Patients with HFPEF tend to be older on average
than those with SHF and in most studies the
majority have been women.
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Etiology and Pathophysiology
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• Risk factors
• Old Age
• HTN with LVH
• ICM with scar formation
• DM
• Restrictive CM
• (Amyloid, sarcoid, EMF)

• Exacerbation triggers
• New onset AF or any SVT
• Sinus Tachycrdia
• (Stress, infection, pain)
• 3. Ischemia

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Pressure-Volume Loop
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Diastolic function has been described as the
passive elastic relaxation properties of the left
ventricle allowing filling of the left ventricle
and systolic function as the active contraction
of the myocardium resulting in ejection of blood
from the left ventricle. Physiologically,
systole and diastole are closely intertwined. In
reality systole and diastole constitute one cycle
and the major determinant of early diastolic
filling is the strength and coordination of the
previous systole, which is the driver for
ventricular suction.
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The misunderstanding of the pathophysiology began
when we defined systolic function solely on the
basis of ejection fraction. Ejection fraction
does not take into account systolic function in
the longitudinal axis. A number of studies have
now shown that LV longitudinal function is
reduced not only in diastole but also in systole
even though LV ejection fraction is within normal
limits. Ejection fraction, the dividing line
between HFPEF and SHF is a continuous variable
and does not completely measure LV systolic
function. Thus there may be comparable
longitudinal LV systolic function between HFPEF
and SHF
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The exact understanding of mechanisms that
contribute to development of HFPEF is still
evolving. However, the main physiological
difference between SHF and HFPEF is the increase
in ventricular volume and change in shape due to
ventricular remodeling. Remodeling leads to
increased ventricular volumes and reduced
ejection fraction. The rate of occurrence of
remodeling is a major differentiating factor.
For example A myocardial infarction (or viral
myocarditis) appears to be a potent stimulant for
the remodeling process resulting in rapid
progression to SHF compared to Hypertensive heart
disease where remodeling is a slower process. In
HHD compensatory increased radial contraction
tends to normalize the ejection fraction however
at later stages further remodeling will occur and
the patient will slip from HFPEF to SHF hence DCM
in burnt out hypertension.
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Thus remodeling is a very important therapeutic
target. Reversing remodeling versus slowing the
rate of the remodeling process will predict
improvement in both systolic and diastolic
function. Some have suggested that if we
understand the pathophysiology basis of diastolic
heart failure, we are free to extend the
application of randomized controlled trial
therapies of systolic heart failure to these
patients
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Clinical Features and Diagnosis
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The diagnosis of Heart failure with Preserved
Ejection Fraction is based on the clinical
finding of congestive heart failure with the
echocardiography findings of preserved left
ventricular ejection fraction and the absence of
valvular abnormalities. (ACC/AHA guidelines)
Although there are clinical differences between
the typical patient presenting with HFPEF and
with SHF these relate more to etiology and
whether remodeling has taken place
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• Establish the presence of heart failure by
  symptoms
• Obtain concentrations of Brain Natriuretic
  Peptide ( /- exercise testing if unsure)
• Determine the presence of diastolic dysfunction,
  ejection fraction and whether remodeling has
  taken place (what are LV volumes)
• Determine the main etiology and mechanisms
  (hypertension (LVH), ischemia, myocarditis,
  infacrtion, infiltration)
• Look for additional deleterious factors
  (dyssynchrony, arrythmias, metabolic/electrolyte
  abnormalities, hospitalizations)

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• B-type BNP is secreted by the ventricles in
  response to increase in ventricular pressure or
  volume stress
• The diagnostic accuracy of BNP increases
  tremendously with inclusion of patients with
  HFPEF
• BNP has reported sensitivity of 91 and
  specificity of 82
• BNP is developing into an exclusion test for
  heart failure however role of BNP for defining
  prognosis and monitoring of therapy still
  requires more investigation

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Mitral Valve inflow

• Normal diastolic dysfunction
• Mild DD impaired relaxation without evidence of
  increased filling pressure
• Moderate DD - impaired relaxation with moderate
  elevation of filling pressures
• Severe DD advanced reduction in compliance

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Ejection Fraction (varies study to
study) Preserved EF gt40 / 50 Reduced EF lt40 /
50 LV volume (normal) M mode - EDD 49 /- 4 mm
ESD 30 /- 5 mm 2 chamber view
EDV 102 /- 18 ml (planemetry) ESV 41 /-
14 ml
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The typical patient with HFPEF is an elderly
woman with a history of hypertension often with
diabetes whose heart failure is episodic often
precipitated by an episode of AF, ischemia or
infection.
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Overlap between SHF and HFPEF
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Management Strategies
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Back to the Case She was treated for ADHF 2/2 new
onset AF that spontaneously converted to NSR in
ED. She was treated with loop diuretics. Her BNP
was elevated, She had a normal CBC, CMP and
cardiac enzymes were not elevated. CXR was c/w
pulm edema. ECHO revealed concentric LVH with
Mild diastolic dysfunction and no wall
abnormalities LVEF was 55. By the time she left
ED she was on 2l NC with pulse Ox of 99. You
observe her on the wards for 24 more hours and
she is stable still in NSR HR 75-80 BP
140-150/80-90 RR 16 on RA. Her BMI is 31. You are
planning to discharge her. In addition to
exercise and salt restriction, what
pharmacotherapy will you institute prior to
discharge??
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• Response to Stress
• Pt with HFPEF tend to have poor response to
  certain stressors
• They tolerate atrial fibrillation (AF) poorly,
  since the loss of atrial contraction can
  dramatically reduce left atrial emptying, LV
  filling, and LV stroke volume.
• They do not tolerate tachycardia well, since the
  increase in heart rate shortens the duration of
  diastole and truncates the important late phase
  of diastolic filling.
• Elevations in systemic blood pressure, especially
  the abrupt, severe, or refractory elevations
  often seen with renovascular hypertension,
  increase left ventricular wall stress, which can
  worsen myocardial relaxation in patients with
  HFPEF
• The acute induction or worsening of diastolic
  dysfunction by ischemia raises left atrial and
  therefore pulmonary venous pressure. This
  explains why many patients with coronary heart
  disease (CHD) and HFPEF may present primarily
  with acute onset shortness of breath, overt
  pulmonary edema and mild or no chest pain. When
  these respiratory symptoms occur in the absence
  of anginal pain, they are often referred to as
  "anginal equivalents."

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Neurohumoral Adaptations Neurohumoral adaptations
exist in both SHF and HFPEF as the compensatory
mechanism the body has. The principal
neurohumoral systems involved in the response to
HF are the sympathetic nervous system and the
reninangiotensinaldosterone system. It is the
long term effects of this adaptation that result
in progression of Heart failure. In principal or
theory, regulation of these systems remains the
hallmark of HF pharmacotherapy although evidence
is still insufficient for patients with HFPEF.
Hormone levels in HF Data from Francis, GS,
Goldsmith, SR, Levine, TB, et al, Ann Intern Med
1984 101370.
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Management principles for patients with diastolic
heart failure
Management principles for patients with diastolic
heart failure, continued
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Evidence
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Control of Hypertension Regression of LVH is an
important therapeutic goal, since it has been
shown to play a significant role in the
pathophysiology of HFPEF
 Effect of therapy with each of five
antihypertensive drug classes on reduction in
left ventricular mass in patients with
hypertension. These data represent a
meta-analysis of 80 trials of over 4100 patients.
The decrease in left ventricular mass index,
adjusted for the duration of therapy and
diastolic pressure, was significantly higher with
angiotensin II receptor blockers (13 percent),
calcium channel blockers (11 percent), and
angiotensin converting enzyme inhibitors (10
percent) compared to beta blockers (6 percent).
Data from Klingbeil, AU, Schneider, M, Martus,
P, et al, Am J Med 2003 11541.
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• Beta-blockers
• Beta blockers have a variety of beneficial
  effects in patients with diastolic HF, including
  slowing the heart rate (which increases the time
  available for both LV filling and coronary flow,
  particularly during exercise), reducing
  myocardial oxygen demand, and, by lowering the
  blood pressure, causing regression of LVH Slowing
  the heart rate is particularly important in the
  treatment of pulmonary congestion due to ischemic
  diastolic HF and for rate control in atrial
  fibrillation.
• Swedish Doppler-echocardiographic study (SWEDIC)
  studied the effect of carvedilol on diastolic
  function variables per doppler ECHO in patients
  with HFPEF. They randomised 113 patients to
  cardvedilol Vs Placebo in double blind multcenter
  fashion. Treatment with carvedilol resulted in a
  significant improvement in EA ratio in patients
  with heart failure due diastolic dysfunction.
  This effect was observed particularly in patients
  with higher heart rates at baseline.

Effect of carvedilol on diastolic function in
patients with diastolic heart failure and
preserved systolic function. Results of the
Swedish Doppler-echocardiographic study (SWEDIC).
AUBergstrom A Andersson B Edner M Nylander E
Persson H Dahlstrom U SOEur J Heart Fail 2004
Jun6(4)453-61.
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• Angiotensin II receptor blockers
• Effect of angiotensin receptor blockade and
  antihypertensive drugs on diastolic function a
  randomised trial. Patients with hypertension and
  evidence of diastolic dysfunction were randomly
  assigned to receive either the angiotensin
  receptor blocker valsartan (titrated to 320 mg
  once daily) or matched placebo. Both groups
  received antihypertensive medication that did not
  inhibit RAAS to target SBP lt135mmHg. The primary
  endpoint was change in diastolic relaxation
  velocity between baseline and 38 weeks as
  determined by tissue doppler imaging. Diastolic
  relaxation velocity increased in both groups
  (Plt0.0001) but there was no significant
  difference in the change in diastolic relaxation
  velocity between the groups (p0.29).
• Lancet. 2007 Jun 23369(9579)2079-87.

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• The best clinical outcomes data among patients
  with diastolic HF come from the CHARM-Preserved
  trial, in which 3023 patients with symptomatic HF
  (almost all NYHA class II or III) and a left
  ventricular EF gt40 percent were randomly assigned
  to either candesartan (mean dose at six months 25
  mg) or placebo. At a median follow-up of 37
  months, there was a small and almost significant
  difference in incidence of the primary end point
  of cardiovascular death or hospitalization for HF
  (22 versus 24 percent adjusted hazard ratio
  0.86 95 CI 0.74-1.00) that was entirely due to
  a significant reduction in hospitalization for HF
  with candesartan (16 versus 18 percent).

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Spironolactone Mottram et al found that
administration of spironolactone for 6 months in
patients with DHF resulted in a reduction in LA
area (which is regarded as a marker of chronic LV
diastolic load). In addition, there was a
decrease in pulmonary venous flow reversal
velocity when compared with placebo, implying a
reduction in LV stiffness and or end-diastolic
pressure. Mottram PM, Haluska B, Leano R, et
al. Effect of aldosterone antagonism on
myocardial dysfunction in hypertensive
patients with diastolic heart failure.
Circulation 2004 Aug 3 110 (5) 558-65 A
prospective, randomized, double-blind trial in
elderly individuals with isolated diastolic
dysfunction using spironolactone 25 mg/day for 4
months demonstrated a significant improvement in
diastolic dysfunction indices measured by
echocardiography.39 Roongsritong C,
Sutthiwan P, Bradley J, et al. Spironolactone
improves diastolic function in the elderly.
Clin Cardiol 2005 Oct 28 (10) 484-7
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• Ongoing trials
• TOPCAT Trial of Aldosterone Antagonist Therapy
  in Adults With Preserved Ejection Fraction
  Congestive Heart Failure. Randomised Double blind
  clinical trial comparing placebo and
  spironolactone Primary outcome Composite of
  hospitalization for the management of heart
  failure and Aborted cardiac arrest.
• The PEP-CHF study39 is a randomised
  placebo-controlled trial of perindopril in 1000
  patients with diastolic heart failure and NYHA
  II-IV. The primary outcome is death and
  heart-failure hospitalisation. Quality of life
  and 6-min walk will also be assessed.
• I-PRESERVE is a randomised placebo-controlled
  trial of irbesartan in 3600 diastolic heart
  failure patients using the primary end point of
  death and hospitalisation due to cardiovascular
  disease.

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• Take home Messages
• HFPEF is common.
• Think about HFPEF in elderly women with DM, HTN
  with new onset SOB.
• The pathophysiology of heart failure based on
  normal Vs reduced LVEF is highly dependant on the
  rate of progression of remodeling.
• Diastolic dysfunction also exists in pt with
  reduced LVEF. Thus there is no such thing as
  diastolic heart failure! (HFSA)
• There is little known about ideal therapies for
  HFPEF except for benefit of ARBs, however the
  therapies for SHF and HFPEF are likely to overlap
  given the pathophysiology.

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• References
• Bernal J, Pitta S et al. Role of
  Renin-Angiotensin-Aldostrerone System in
  diastolic Heart Failure. Am J Cardiovasc Drugs
  2006 6 (6) 373-381
• Francesca Bursi Susan A. Weston Margaret M.
  Redfield et al. Systolic and Diastolic Heart
  Failure in the Community. JAMA.
  2006296(18)2209-2216
• J E Sanderson. Heart failure with a normal
  ejection fraction. Heart 200793155-158
• Stefano Ghio, Giulia Magrini, Alessandra Serio et
  al. Effects of nebivolol in elderly heart failure
  patients with or without systolic left
  ventricular dysfunction results of the SENIORS
  echocardiographic substudy. European Heart
  Journal (2006) 27, 562568
• E. B. WU, C. M. YU et al. Management of diastolic
  heart failure a practical review of
  pathophysiology and treatment trial data. Int J
  Clin Pract, October 2005, 59, 10, 12391246
• Hans Persson et al. Diastolic Dysfunction in
  Heart Failure With Preserved Systolic Function
  Need for Objective Evidence. Results From the
  CHARM Echocardiographic SubstudyCHARMES. JACC
  Vol. 49, No. 6, 200768794
• Takeshi Tsujino et al. Left Ventricular Diastolic
  Dysfunction in Diabetic Patients Pathophysiology
  and Therapeutic Implications. Am J Cardiovasc
  Drugs 2006 6 (4) 219-230
• Mottram PM, Haluska B, Leano R, et al. Effect of
  aldosterone antagonism on myocardial dysfunction
  in hypertensive patients with diastolic heart
  failure. Circulation 2004 Aug 3 110 (5) 558-65
• Wachtell K, Bella JN, Rokkedal J, et al. Change
  in diastolic left ventricular filling after one
  year of antihypertensive treatment the Losartan
  Intervention For Endpoint Reduction in
  Hypertension (LIFE) Study. Circulation 2002 Mar
  5105 (9) 1071-6
• Harrisons Principles of Internal Medicine

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Thanks