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Heart Failure with Preserved Ejection Fraction HFPEF Senior Talk

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									   Senior Talk

Gilbert-Roy Kamoga

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?
Heart Failure with Preserved Ejection Fraction

► 1.   Definition of HFPEF
► 2.   Describe the Epidemiology
► 3.   Elaborate on Pathophysiology
► 4.   Clinical Features and Diagnosis
► 5.   Management Strategies
► 6.   Take home Message
  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)
Population based prevalence studies suggest that nearly half
         the patients with heart failure have HFPEF

  The 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
      LVEF > 0.45 but only 55% had an LVEF > 0.55
   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.
 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.
Patients with HFPEF tend to be older on average than
those with SHF and in most studies the majority have
                   been women.
Etiology and Pathophysiology
         Risk factors          Exacerbation triggers
1. Old Age                   1. New onset AF or any
2. HTN with LVH
                             2. Sinus Tachycrdia
3. ICM with scar formation
                               (Stress, infection, pain)
4. DM
                             3. Ischemia
5. Restrictive CM
  (Amyloid, sarcoid, EMF)
                  Pressure-Volume Loop
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.
 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
 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.
  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
Clinical Features and Diagnosis
  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
                    (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
 1. Establish the presence of heart failure by symptoms
2. Obtain concentrations of Brain Natriuretic Peptide ( +/-
                exercise testing if unsure)
   3. Determine the presence of diastolic dysfunction,
    ejection fraction and whether remodeling has taken
                place (what are LV volumes)
     4. Determine the main etiology and mechanisms
   (hypertension (LVH), ischemia, myocarditis, infacrtion,
5. Look for additional deleterious factors (dyssynchrony,
     arrythmias, metabolic/electrolyte abnormalities,
•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
                          Mitral Valve inflow
1. Normal diastolic dysfunction
2. Mild DD – impaired relaxation without evidence of increased filling
3. Moderate DD - impaired relaxation with moderate elevation of filling
4. Severe DD – advanced reduction in compliance
        Ejection Fraction
         (varies study to study)

     Preserved = EF >40 / 50
      Reduced = EF <40 / 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
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.
Overlap between SHF and HFPEF
Management Strategies
                        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

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??
                               Response to Stress
       Pt with HFPEF tend to have poor response to certain stressors
1. They tolerate atrial fibrillation (AF) poorly, since the loss of atrial contraction can
      dramatically reduce left atrial emptying, LV filling, and LV stroke volume.
2. 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
     3. 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
4. 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."
                           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 renin–angiotensin–aldosterone
    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; 101:370.
                                   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; 115:41.
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 E:A ratio in patients with heart failure due diastolic dysfunction.
   This effect was observed particularly in patients with higher heart rates at
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 Jun;6(4):453-61.
                   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 <135mmHg. 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 (P<0.0001) but
 there was no significant difference in the change in diastolic relaxation velocity
                            between the groups (p=0.29).
                                                       Lancet. 2007 Jun 23;369(9579):2079-87.
•  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 >40 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).

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

 Roongsritong C, Sutthiwan P, Bradley J, et al. Spironolactone improves diastolic function in the elderly.
 Clin Cardiol 2005 Oct; 28 (10): 484-7
                               Ongoing trials

1. 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.
2. The PEP-CHF study[39] 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.
3. 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.
                 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”!
• 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.
1.   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
2.   Francesca Bursi; Susan A. Weston; Margaret M. Redfield; et al. Systolic and Diastolic Heart
     Failure in the Community. JAMA. 2006;296(18):2209-2216
3.   J E Sanderson. Heart failure with a normal ejection fraction. Heart 2007;93;155-158
4.   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, 562–568
5.   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, 1239–1246
6.   Hans Persson et al. Diastolic Dysfunction in Heart Failure With Preserved Systolic Function:
     Need for Objective Evidence. Results From the CHARM Echocardiographic Substudy–CHARMES.
     JACC Vol. 49, No. 6, 2007:687–94
7.   Takeshi Tsujino et al. Left Ventricular Diastolic Dysfunction in Diabetic Patients:
     Pathophysiology and Therapeutic Implications. Am J Cardiovasc Drugs 2006; 6 (4): 219-230
8.   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
9.   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 5;105 (9): 1071-6
10. Harrison’s Principles of Internal Medicine

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