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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?

Heart Failure with Preserved Ejection Heart Failure with Preserved Ejection FractionFraction

(HFPEF)(HFPEF)

ObjectivesObjectives

► 1. Definition of HFPEF1. Definition of HFPEF► 2. Describe the Epidemiology2. Describe the Epidemiology► 3. Elaborate on Pathophysiology3. Elaborate on Pathophysiology► 4. Clinical Features and Diagnosis4. Clinical Features and Diagnosis► 5. Management Strategies5. Management Strategies► 6. Take home Message6. Take home Message

DefinitionDefinition

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)

EpidemiologyEpidemiology

Population based prevalence studies suggest that Population based prevalence studies suggest that nearly half the patients with heart failure have HFPEFnearly half the patients with heart failure have HFPEF

The proportion of the patients with HFPEF in the The proportion of the patients with HFPEF in the various studies ranges from 40-71% (mean 56%). various studies ranges from 40-71% (mean 56%). These prevalence studies are compromised by the These prevalence studies are compromised by the

precise threshold for what is considered to be a precise threshold for what is considered to be a normal Left Ventricular Ejection Fraction.normal Left Ventricular Ejection Fraction.

One study elaborated that 80% of heart failure One study elaborated that 80% of heart failure patients had an patients had an

LVEF > 0.45 but only 55% had an LVEF > 0.55LVEF > 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

1. Old Age

2. HTN with LVH

3. ICM with scar formation

4. DM

5. Restrictive CM

(Amyloid, sarcoid, EMF)

Exacerbation triggers

1. New onset AF or any SVT

2. Sinus Tachycrdia

(Stress, infection, pain)

3. Ischemia

http://www.pharmacology2000.com/cardiac/P-V_animation_gif.gif

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 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

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, infiltration)

5. Look for additional deleterious factors (dyssynchrony, arrythmias, metabolic/electrolyte

abnormalities, hospitalizations)

•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

1. Normal diastolic dysfunction

2. Mild DD – impaired relaxation without evidence of increased filling pressure

3. Moderate DD - impaired relaxation with moderate elevation of filling pressures

4. Severe DD – advanced reduction in compliance

Mitral Valve inflow

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 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??

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 filling.

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 HFPEF

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.

Evidence

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

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 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 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).

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

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”! (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.

References1. 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

Thanks