**2.2 The diagnosis of DHF**

The diagnosis of heart failure with normal left ventricular (LV) ejection fraction (HFNEF) requires the following conditions to be satisfied: (1) signs or symptoms of heart failure; (2) normal or mildly abnormal systolic LV function; (3) evidence of diastolic LV dysfunction. Normal or mildly abnormal systolic LV function implies both an LVEF > 50% and an LV end-diastolic volume index (LVEDVI) < 97 mL/m2. Diagnostic evidence of diastolic LV dysfunction can be obtained invasively (LV end-diastolic pressure >16 mmHg or mean pulmonary capillary wedge pressure >12 mmHg) or non-invasively by tissue Doppler (TD) (E/E' >15) with an echocardiography. If TD yields an E/E' ratio suggestive of diastolic LV dysfunction ( 8 < E/E' < 15 ), additional non-invasive investigations are required for diagnostic evidence of diastolic LV dysfunction. These can consist of blood flow Doppler of mitral valve or pulmonary veins, echocardiographic measures of LV mass index or left atrial volume index, electrocardiographic evidence of atrial fibrillation, or plasma levels of natriuretic peptides. If plasma BNP is more than 200 pg/mL, diagnostic evidence of diastolic LV dysfunction also requires additional non-invasive investigations (Fig. 1).

LVEDVI: left ventricular end-diastolic volume index, mPCW: mean pulmonary capillary wedge pressure, LVEDP: left ventricular end-diastolic pressure, TD: tissue Doppler, E: early mitral valve flow velocity, E': early TD lengthening velocity, BNP: brain natriuretic peptide, E/A: ratio of early (E) to late (A) mitral valve flow velocity, Dct: deceleration time, LVMI: left ventricular mass index; LAVI: left atrial volume index, Ard: duration of reverse pulmonary vein atrial systole flow, Ad: duration of mitral valve atrial wave flow.

disease (CAD) showed structural and functional differences in cardiomyocytes from patients with diastolic HF compared to cardiomyocytes from patients with abnormal systolic ejection fraction.[8] Myocytes from patients with diastolic HF had increased diameter and higher myofibrillar density and developed greater passive force and had greater calcium sensitivity. Myocardial collagen volume fraction was equally elevated.

Patients with DHF were shown to have similar pathophysiological characteristics, compared with HF patients with a reduced EF including reduced exercise capacity and impaired quality of life. The Framingham criteria for diagnosis of HF is the following. Major criteria are 1) paroxysmal nocturnal dyspnea or orthopnea, 2) jugular venous distention (or central venous pressure is more than 16 mmHg), 3) hearing rale or acute pulmonary edema, 4) cardiomegaly, 5) hepatojuglar reflex, and 6) response to diuretics (weight loss is more than 4.5 kg per 5 days). Minor criteria are 1) ankle edema, 2) nocturnal cough, 3) exertional dyspnea, 4) pleural effusion, 5) vital capacity lower less than two thirds of normal condition, 6) hepatomegaly, and 7) tachycardia (more than 120 beats/minute. With diastolic HF, fourth heart sounds may be present but third heart sounds are seldom present. Chest radiography will show pulmonary congestion during acute exacerbations and for some time following an episode, cardiomegaly will be present in systolic HF but may or may not be present in HF with preserved ejection fraction. When it is difficult with diagnosing HF, it is important to

The diagnosis of heart failure with normal left ventricular (LV) ejection fraction (HFNEF) requires the following conditions to be satisfied: (1) signs or symptoms of heart failure; (2) normal or mildly abnormal systolic LV function; (3) evidence of diastolic LV dysfunction. Normal or mildly abnormal systolic LV function implies both an LVEF > 50% and an LV end-diastolic volume index (LVEDVI) < 97 mL/m2. Diagnostic evidence of diastolic LV dysfunction can be obtained invasively (LV end-diastolic pressure >16 mmHg or mean pulmonary capillary wedge pressure >12 mmHg) or non-invasively by tissue Doppler (TD) (E/E' >15) with an echocardiography. If TD yields an E/E' ratio suggestive of diastolic LV dysfunction ( 8 < E/E' < 15 ), additional non-invasive investigations are required for diagnostic evidence of diastolic LV dysfunction. These can consist of blood flow Doppler of mitral valve or pulmonary veins, echocardiographic measures of LV mass index or left atrial volume index, electrocardiographic evidence of atrial fibrillation, or plasma levels of natriuretic peptides. If plasma BNP is more than 200 pg/mL, diagnostic evidence of diastolic LV dysfunction also requires additional non-invasive investigations

LVEDVI: left ventricular end-diastolic volume index, mPCW: mean pulmonary capillary wedge pressure, LVEDP: left ventricular end-diastolic pressure, TD: tissue Doppler, E: early mitral valve flow velocity, E': early TD lengthening velocity, BNP: brain natriuretic peptide, E/A: ratio of early (E) to late (A) mitral valve flow velocity, Dct: deceleration time, LVMI: left ventricular mass index; LAVI: left atrial volume index, Ard: duration of reverse

pulmonary vein atrial systole flow, Ad: duration of mitral valve atrial wave flow.

**2.1 Characteristics of medical examination** 

use echocardiography. [9,10]

**2.2 The diagnosis of DHF** 

(Fig. 1).

Fig. 1. How to diagnose HFNEF: Diagnostic flow chart in a patient suspected of HFNEF.

A similar strategy with focus on a high negative predictive value of successive investigations is proposed for the exclusion of HFNEF in patients with breathlessness and no signs of congestion. If a patient with breathlessness and no signs of fluid overload has a BNP of less than 100 pg/mL, any form of heart failure is virtually ruled out because of the high negative predictive value of the natriuretic peptides, and pulmonary disease becomes the most likely cause of breathlessness (Fig. 2). [11,12]

As far as diastolic dysfunctuion, in decompensated patients with advanced systolic heart failure (LVEF≦30%, New York Heart Association class Ⅲ to Ⅳ symptoms), tissue Dopplerderived with E/E' ratio may not be as reliable in predicting intracardiac filling pressures, particularly in those with larger LV volumes, more impaired cardiac indices, and the presence of cardiac resynchronization therapy. [13]

Diastolic Heart Failure 53

C

D

Fig. 3. Normal pattern in LV inflow: Panel A shows long axis view. Panel B shows 4 chamber view. Panel C shows LV inflow. Panel D shows tissue Doppler imaging.

Fig. 4. Abnormal relaxation pattern in LV inflow: Panel A shows long axis view. Panel B shows 4 chamber view. Panel C shows LV inflow. Panel D shows tissue Doppler imaging.

Most patients with HF preserved EF have normal chamber dimensions, although a small

A B

C D

**2.3.2 Left ventricle in diastolic heart failure** 

subset may have variable degrees of LV enlargement.

A

B

Fig. 2. How to exclude HFNEF: Diagnostic flow chart in a patient presenting with breathlessness and no signs of fluid overload.

#### **2.3 Echocardiography in diastolic heart failure**

#### **2.3.1 Doppler echocardiographic assessment of diastolic function and filling pressures**

Comprehensive Doppler echocardiography is invaluable in the evaluation of HF patients as the 2.1. characteristics of medical examination section. Assessment of diastolic function begins with the transmitral flow velocity profile. Decreases in the ratio of early to late diastolic filling (E/A), increases in the deceleration time, increases in the isovolumic relaxation time, or increases in tissue Doppler imagings (E/E') indicate impaired relaxation. However, in the presence of impaired relaxation, increases in filling pressure progressively modify the transmitral gradient and mitral inflow pattern. A comprehensive Doppler assessment must be used to determine diastolic function from filling pressures and tissue Doppler imagings. [12] Patients studied at various times during their presentation will display a spectrum of filling patterns, including abnormal relaxation and psuedonormal or restrictive patterns. Such a spectrum has also been reported in patients with HF with a depressed EF and reflects the potent effect of filling pressures and blood pressure and their interaction with underlying diastolic dysfunction on the Doppler patterns. Thus, depending on their level of compensation and their filling pressures and whether they have exertional or rest symptoms, patients with HF preserved EF may display any of the filling patterns.[14]

BNP > 100 pg/ml

Consider HFREF

Consider high output state

Consider HFNEF

Consider coronary artery disease with Deficient angina warning

Evidence of pulmonary disease

Yes Consider pulmonary disease

Consider valvular or pericardial disease Yes

Breathlessness, without signs of fluid overload

No

Fig. 2. How to exclude HFNEF: Diagnostic flow chart in a patient presenting with

**2.3.1 Doppler echocardiographic assessment of diastolic function and filling** 

Comprehensive Doppler echocardiography is invaluable in the evaluation of HF patients as the 2.1. characteristics of medical examination section. Assessment of diastolic function begins with the transmitral flow velocity profile. Decreases in the ratio of early to late diastolic filling (E/A), increases in the deceleration time, increases in the isovolumic relaxation time, or increases in tissue Doppler imagings (E/E') indicate impaired relaxation. However, in the presence of impaired relaxation, increases in filling pressure progressively modify the transmitral gradient and mitral inflow pattern. A comprehensive Doppler assessment must be used to determine diastolic function from filling pressures and tissue Doppler imagings. [12] Patients studied at various times during their presentation will display a spectrum of filling patterns, including abnormal relaxation and psuedonormal or restrictive patterns. Such a spectrum has also been reported in patients with HF with a depressed EF and reflects the potent effect of filling pressures and blood pressure and their interaction with underlying diastolic dysfunction on the Doppler patterns. Thus, depending on their level of compensation and their filling pressures and whether they have exertional or rest symptoms, patients with HF preserved EF may display any of the filling patterns.[14]

No

No No

No

Yes Echocardiography No

Evidence of valvular or pericardial disease No LVEF > 50%

> Yes LVEDVI < 76 mL/m2

Yes LAVI < 29 mL/m2 and no Atrial Fibrillation Yes

LVMI < 96 g/m2 (women),< 116 g/m2 (men)

E/E' < 8

Yes No HFNEF

TD Yes

breathlessness and no signs of fluid overload.

**pressures** 

**2.3 Echocardiography in diastolic heart failure** 

Fig. 3. Normal pattern in LV inflow: Panel A shows long axis view. Panel B shows 4 chamber view. Panel C shows LV inflow. Panel D shows tissue Doppler imaging.

Fig. 4. Abnormal relaxation pattern in LV inflow: Panel A shows long axis view. Panel B shows 4 chamber view. Panel C shows LV inflow. Panel D shows tissue Doppler imaging.

#### **2.3.2 Left ventricle in diastolic heart failure**

Most patients with HF preserved EF have normal chamber dimensions, although a small subset may have variable degrees of LV enlargement.

Diastolic Heart Failure 55

determinant of ventricular filling pressure. In spite of chronic data are lacking on nitrates, they are effective on the diastolic HF in the acute phase, because of deceasing central blood volume by vasodilating. In spite of chronic data are also lacking on human atrial natriuretic peptides, they are effective on the diastolic HF in the acute phase, because of deceasing central blood volume by natriuretic and vasodilating effect. Digoxin was reported to yield symptomatic improvement and decreased hospitalizations without mortality benefit in the

We treat with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and aldosterone antagonists in the chronic systolic heart failure patients, because the rennin-angiotensin- aldosterone system (RAAS) plays the pivotal roles on the left ventricular remodeling in HF patients.[25] Recent studies of HF patients with preserved LV function suggest that ACE inhibitors or ARBs may improve functional class, exercise duration, ejection fraction, diastolic filling and LV hypertrophy. In the large randomized trial of perindopril (an ACE inhibitor) for patients older than 70 years with chronic HF and normal or near-normal EF, event rates were lower than anticipated. Some trends toward benefit, primarily driven by reduction in HF-related hospitalizations, were observed at 1 year (PEP-CHF trial).[26] In the CHARM-Preserved Trial, [27] HF patients with an EF higher than 40% were randomized to candesartan ( an angiotensin receptor antagonist ) or placebo in addition to standard therapy. Fewer patients in the candesartan group than in the placebo group reached the primary endpoint of cardiovascular death or HF hospitalization, a finding that reached statistical significance only after adjustment for nonsignificant differences in baseline characteristics. Then, irbesartan (an ARB) did not improve the outcomes of DHF patients (I-PRESERVE).[28] Although candesartan and irbesartan are angiotensin receptor blockers, the results of the trials are different. These pleiotropic effects may be different. The trial of aldosterone antagonists for DHF patients is going on in DHF patients (TOPCAT trial). Beta blocker has been shown to improve morbidity with diastolic and systolic HF. [29,30] Although calcium channel antagonists can improve measures of diastolic function during short-term use, definitive data with chronic administration for diastolic HF are not available. Recent reports show statins reduce the number of cardiovascular hospitalizations in patients with systolic heart failure, although they did not reduce the primary outcome which is the composite of death from cardiovascular causes, non fatal myocardial infarction and nonfatal stroke.[31,32] A few trials of statins have shown to improve the mortality in patients with DHF [33]. Further investigations are

Heart failure with normal left ventricular ejection fraction (HFNEF) currently accounts for more than 50% of all heart failure patients. The updated strategies for the diagnosis and exclusion of HFNEF are useful not only for individual patient management but also for

The authors thank Dr. Takahiro Shiota, MD (Professor, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center and UCLA, Los Angels, USA), Dr. Homma Shunichi, MD, FACC (the

patient recruitment in future clinical trials exploring therapies for HFNEF.

DIG study in patients with DHF.[24]

needed.

**3. Conclusions** 

**4. Acknowledgments** 

Although HF preserved EF has been thought to occur primarily inpatients with LVH, studies that have carefully quantified LV mass report that echocardiographic criteria for LVH are met in less than 50% of patients. [15-18]
