Diastolic Dysfunction and Heart Failure With a Preserved Ejection Fraction Relevance in Critical...

Diastolic dysfunction and heart failure with

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P.O. Box 2925 Riyadh 11461KSATel: +966 1 2520088 ext 40151Fax: +966 1 2520718Email: [email protected]: www.sha.org.sa

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10167315 2012 King Saud University.Production and hosting by Elsevier B.V. All rights reserved.Received 29 September 2011; revised 22 January 2012; accepted 23 JanuaryMethodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100Pathophysiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Cardiomyocyte . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101Extracellular matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103Age related changes in diastolic function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Assessment of diastolic function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105Anaesthetic implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

Pre-operative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106Exercise capacity and diastolic dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106Implications in the perioperative period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106Diastolic dysfunction and sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108Pediatric patients with cardiac disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109Diastolic dysfunction and medical disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

Renal disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110eywords: Diastolic dysfunction, HF with preserved ejection fraction, Sepsis, Anaesthesia, Diabetes, Paediatrics,enal 2012 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.lness.

lic dysfunction and HF with a preserved ejection fraction during the perioperative period and during criticalclearer understanding of the underlying pathophysiology and clinical implications of HF with a preserved ejectionaction is fundamental to directing further research and to evaluate interventions. This review highlights the impact ofiastoEpidemiological and clinical studies suggest that HF with a preserved ejection fraction will become the moreommon form of HF which clinicians will encounter. The spectrum of diastolic disease extends from the asymptomatichase to fulminant cardiac failure. These patients are commonly encountered in operating rooms and critical care units.tment of Intensive Care Medicine, Kings College Hospital, London SE5 9RS, UKPeer review under responsibility of King Saud University.

URL: www.ksu.edu.sa

doi:10.1016/j.jsha.2012.01.004

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Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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tion. This review aims is to describe the patho-

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The concept of HFpreEF was introduced by

ever, there may be several limitations to this defi-nition. Specifically elevated BNP levels have been

the absence of congestive heart failure (CHF)

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100 MAHARAJDIASTOLIC DYSFUNCTION AND HEART FAILURE

J Saudi Heart Assoc2012;24:99121odology

e literature review was obtained from a com-

vated BNP may be through up regulation of theventricular BNP expression or by transient in-creases in left ventricular wall stress [25,26]. TheLVEF most widely accepted as a threshold valueFpreEF. [24,25], renal failure, and obesity. The proposedmechanism by which ischaemia results in ele-clinical relevance of diastolic dysfunction and

physiological mechanisms for and highlight the found in patients with myocardial ischaemia inConflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Over five million people in the United Stateshave chronic HF (HF) and about five hun-dred thousand new cases are reported every year[13]. Epidemiological and clinical studies haveconfirmed the trend of increasing incidence ofchronic HF internationally [4]. HF remains largelya disease of the elderly and in patients older than65 years it is the most common diagnosis at hospi-tal discharge and the most frequent cause of re-admission [3,5]. Diastolic dysfunction refers toabnormalities in left ventricular distensibility, fill-ing or relaxation regardless of signs and symp-toms of HF or left ventricular ejection fraction[6]. Diastolic dysfunction in the absence of symp-toms is common in elderly hypertensive patients[7]. Heart failure with a preserved ejection fraction(HFpreEF), or diastolic HF, refers to the clinicalsyndrome of HF coupled with evidence of dia-stolic dysfunction and is estimated to occur inapproximately 50% of patients with chronic HF[812]. In patients older than 70 years, the ad-justed mortality rate for HFpreEF is equivalent tothose patients with reduced systolic function [812]. It is projected that in the developed worldthe proportion of the population >65 years oldand the number of surgical procedures in thisgroup of patients will increase dramatically withat least one in two persons undergoing an opera-tion in the remainder of their lifetime [13]. It istherefore imperative that anaesthetists andintensivists appreciate the impact of diastolic dys-function and HFpreEF on the aging heart. Despiterecent advances in the understanding of HF, thereis little consensus about the definition, prognosisand treatment of HFpreEF and diastolic dysfunc-Chronic obstructive airways disease (COPD) . . . . . . . . . . . .Cirrhotic cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . .Is diastolic heart failure a precursor to the evolution of systor search of the PUBMED, MEDLINE andASE databases from 1966 to DecemberKessler in 1988 [14]. Subsequently, there havebeen numerous attempts to develop diagnosticcriteria; however there has been little consensus[1519]. In 1998 Paulus et al. developed the Euro-pean Criteria for HFpreEF [20]. This group sug-gested that there must be objective evidence ofHF with a normal or mildly impaired systolic func-tion (left ventricular ejection fraction(LVEF) > 45%) and abnormal left ventricular (LV)relaxation. All three criteria are required for thediagnosis of HFpreEF. Plasma levels of B-natri-uretic peptide (BNP) are elevated in patients withHF, independent of the aetiology of HF [21,22]. Analternative and simpler definition of HFpreEF isan elevated BNP with a normal LVEF [23], how-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112heart failure or a syndrome on its own? . . . . . . . . . . . . . . . . . . . . 112. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

2011. A number of different search strategies wereused and articles were restricted to English lan-guage only. Search terms included diastolic, dys-function, heart failure, sepsis, critical illness,paediatrics, pre-operative, post-operative,diabetes, renal impairment and anaesthesia.This is a narrative review as the broad spectrumof topics covered in this review prohibits a fullysystematic approach. Abstracts were screened forrelevance. Additional reports were identified fromreference list screening and relevant systematicreviews were sought and their findings high-lighted. Authors were not contacted for additionalinformation.

Definitionis >50%. Diastolic dysfunction refers to impairedLV filling capacity due to abnormalities in

ft panel) and in diastolic dysfunction (right panel). The diastolic pressuren of the LV is unchanged.

Table 1. The European Society of Cardiology Criteria forDiastolic Heart Failure [29].

The European consensus criteria for diastolic HF

1. Signs and symptoms of CHFEffort dyspnoea, orthopnea, pulmonary rales/oedema.Cardiopulmonary exercise testing (VO2 max< 25 ml/kg/min)

2. Normal or mildly reduced ejection fraction andnormal chamber sizeLVEF > 50% andNormal LV end diastolic volume(122 g/m2 or an LV wall mass index>149 g/m2, in the presence of symptoms, adequateevidence for the diagnosis of diastolic HF whenother modalities such as Tissue Doppler Imaging(TDI) are inconclusive in the context of elevatedBNP levels [29].

Pathophysiology

The four phases of diastolic function are de-picted in Fig. 2. The optimal LV pressure curvewould be rectangular allowing the maximal timefor ventricular filling [30]. The structural, func-tional and molecular mechanisms involved in dia-stolic dysfunction can conceptually be divided inthose that occur at the cardiomyocyte level andthose that are extrinsic to the myocyte [28,29].Cardiomyocyte

At the myocyte level, changes in calciumhomeostasis result in an increased diastolic cyto-solic calcium. This may be as a result of (1) abnor-malities in the sarcoplasmic reticulum calcium (SRCa2+) reuptake due to decreases in SR Ca2+ ATP-ase (2) abnormalities in the ionic channels respon-sible for calcium transport, and (3) changes in thestate of phosphorylation of proteins such as phos-pholamban, calmodulin and calsequestrin thatmodify SR Ca2+ ATPase function [31,32]. Increasedcytosolic calcium causes abnormalities in both ac-tive relaxation and passive stiffness [33].

distensibility or stiffnessEchocardiographic: Tissue Doppler (E/Ea > 15)

LA volume P34 ml/m2 if E/Ea between 9 and 14Cardiac catheterisation: LVEDP > 16 mmHgBiomarkers NT-proBNP > 220 pg/ml or BNP > 200 pg/ml

All three criteria are required for the diagnosis of diastolic heart failure.

marthaslore.

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J Saudi Heart Assoc2012;24:99121Troponin I, T and C are bound to actin. Myocar-dial relaxation is an active process and ATPhydrolysis is required for actin-myosin separa-tion, calcium dissociation from Tn-C and calciumsequestration by the SR [34]. The sensitivity ofthe myofilament to calcium has recently been re-viewed by Kass et al. [35]. Current evidence sup-ports a modified theory of excitationcontractioncoupling that myosin cross bridges binds weaklyto the actin filament in the relaxed state and cre-ates a closed state [36]. In this closed state the

Figure 2. The four phases of diastole. The first point of intersectionopening. In the rapid filling phase the left atrial (LA) pressure is higherpressure exceeds LA pressure resulting in decelerating flow. During thechambers. Atrial contraction raises the LA pressure above the LV pressuE wave seen on transmitral flow.cross-bridging interaction creates a non-force gen-erating reaction [37] Troponin I is necessary totether the actin and maintain diastole. Altered tro-ponin I function can produce diastolic dysfunction[38].

Data from explanted hearts and other models ofHF show a shift towards higher intracellular Na+

[3943]. The consequence of this high [Na+]i iscytosolic Ca2+ overload and alterations in cellgrowth and metabolism, which in turn result inselective abnormalities in diastolic function [3943].

Abnormalities in myocardial phosphate metab-olism also influence diastolic function. Normaldiastolic function requires that the concentrationof the products of ATP hydrolysis, ADP and inor-ganic phosphate [Pi], must remain low and pro-duce the appropriate relative ADP/ATP ratio[23,4447]. Diastolic dysfunction may occur if theabsolute concentration of ADP increases or the[48] phosphocreatine/ATP ratio decreases. Studiesin isolated heart models have also demonstrateddiastolic dysfunction coupled to metabolic inhibi-tion or ischaemia linked to increased free ADP[49].

The cardiomyocyte cytoskeleton is composed ofmicrotubules, intermediate filaments (desmin),microfilaments and endosarcomeric proteins (ti-tin, nebulin, alpha-actin, myomesin and M-pro-tein) [50]. Changes in the cytoskeleton proteinsmay alter diastolic function [5153]. The sarco-meric macromolecule titin has been recognizedas a major determinant of both viscoelastic stiff-ness and relaxation [54]. Titins span the entire sar-

ks the end of the isovolumic relaxation (IR) phase and mitral valven the left ventricular (LV) pressure. The second pont of intersection LVw filling phase there is almost no pressure difference between the twoThe period between the first two intersection points corresponds to thecomere extending from the Z-line to the centre ofthe sarcomere [55]. During contraction, potentialenergy is gained when titin is compressed. Duringdiastole, titin acts like a spring and expends thispotential energy, providing a recoiling force to re-store the myocardium to its resting length [55,56].Titin also protects the myocardium from beingstretched beyond the resting length [52,55]. Titinis expressed in two isoforms: a smaller, stifferN2B and a larger, more compliant N2BA. The ratioof N2BA to N2B is reduced in DHF [55,57]. Themechanisms involved in isoform switching arepoorly understood but probably relate to chronicpressure overloading [55,57]. Pressure overloadmay increase microtubule density and distribu-tion and increase myocardial stiffness.

A seminal paper by Selby et al. was amongst thefirst to use a LV biopsy sample obtained duringcoronary artery bypass surgery to examine tachy-cardia-induced relaxation abnormalities in pa-tients with a normal ejection fraction [58]. Tissuesamples obtained from patients with left ventricu-lar hypertrophy (LVH) had some evidence of

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MAHARAJ 103DIASTOLIC DYSFUNCTION AND HEART FAILURETable 2. Studies comparing systolic and diastolic heart failure (

Author Year EF (%) Number ofpatients (%DHF)

Follow

Smith [105] 2003 40 413 (48%) 6 monVasan [8] 1999 50 73 (51%) 5 yrCohn [106] 1990 45 623 (13%) 1 yrAnsari [108] 2003 45 147 (44%) 22 moSenni [258] 1998 50 59 (43%) 1 yr

5yBhatia [109] 2006 50 2802 (30%) 1 yr

Table 3. Criteria used to define diastolic dysfunction (modified

Criteria Normal adult Impairedrelaxation(stage 1)

Pseudonor

E/A ratio 12 240 150200

IVRT (ms) 7090 >90 1 >1 45 8

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J Saudi Heart Assoc2012;24:99121Assessment of diastolic function

Echocardiography

The ideal method to assess diastolic functionshould be widely available, easy to interpret andaccurate. Unfortunately this remains elusive andall existing methods have limitations. Invasivetechniques have largely been replaced by echo-cardiography. The reference ranges for the echo-Age related changes in diastolic functionDuring aging, changes related to increased myo-

cardial and ventricular stiffening and diminishedb-adrenergic receptor responsiveness are highlysignificant. At the myocyte level, age-relatedreductions in SERCA2 levels and activity resultin abnormal diastolic sequestration of calcium[7174]. An increase in activity of phospholambanalso impairs diastolic function. Aging is associatedwith a b-adrenergic associated signal dampening[75,76]. This may be due to receptor down-regula-tion or due to reduced receptor coupling to adenylcyclase via Gs proteins. There is some evidencethat the adrenergic receptor density changes withage with a decrease in high affinity b-receptor[77,78]. There is also an age related increase inmyocyte size but decrease in myocyte number[79]. At the extracellular matrix level there is anage-related interstitial fibrosis as a result of in-creases in fibrin, fibronectin and collagen. Age re-lated degeneration of the conducting systemmakes elderly patients prone to arrhythmia andfurther compromises diastolic function [80]. Agingis associated with systolic-ventricular and arterialstiffening [8184], which may influence diastolicfunction in several ways. Arterial stiffening in-creases myocardial oxygen consumption for a gi-ven stroke volume and ventricular systolicstiffening exacerbates this effect. Energy costsare predicted to be >50% higher in patients withHfpreEF than controls [85]. The increased arterialstiffness results in ventricular hypertrophy to pre-serve systolic function at the expense of left ven-tricular compliance and filling [84,86].TIMP is altered in HF. TIMP-1 is downregulatedin myocardial ischaemia. TIMP-4 is upregulatedin hypertension. A deficiency in TIMP-3 may bedirectly related to cardiac remodeling and the evo-lution of HF [70]. The specific contribution thatTIMP makes to diastolic dysfunction is unresolvedand a better understanding of this complex pro-tein in HF is warranted.cardiography variables used have been derivedfrom studies employing transthoracic echocardi-ography (TTE). However in the perioperativeand critical care context TTE is often technicallychallenging. This may be due to difficulties withpatient positioning, or a reduction of the acousticwindow by high levels of positive end expiratorypressure, the presence of injuries, drains ordressings on the precordial area [87,88]. Trans-esophageal echocardiography (TEE) has been rec-ommended to overcome these limitations [89].The reference ranges are derived from awake pa-tients undergoing TTE in the lateral decubitus po-sition. This is in contrast to the supineanaethetised patient receiving mechanical ventila-tion under dynamic haemodynamic conditionsinfluenced by anaesthetic drugs [9093]. A com-prehensive review on the perioperative assess-ment of diastolic function has recently beenpublished and the reader is referred here [93]. Asummary of the criteria commonly used to definediastolic dysfunction is presented in Table 3 [30].The mitral inflow velocity is one of the earlyechocardiographic indices used to define diastolicdysfunction. Early transmitral inflow is denoted asE velocity and depends on left atrial compliance,left ventricle compliance, the rate of left ventriclerelaxation and the suction effect created by thebase to apex intraventricular pressure gradient at-rial contraction is represented by the A velocityand is influenced by left atrial contractility and leftventricular compliance. The deceleration time(DT) is the time interval between the peak of theE wave to baseline and represents the time forequalization of pressure between the left atriumand ventricle (Fig. 2). While mitral inflow veloci-ties are easily obtained, they are highly preloaddependant and problematic in patients with atrialfibrillation. Diastolic dysfunction results in de-layed transfer of blood from atrium to ventricle.The atrium responds by emptying more vigor-ously and soon accounts for the dominant compo-nent of left ventricular filling. In response tochronic increased left atrial impedance, the atriumundergoes enlargement. As diastolic dysfunctionevolves further the atrial pressure increases andthe DT decreases, the E/A ratio and the DT appearnormal (grade II). With further deterioration ofdiastolic function the E/A ratio may exceed 2 andthe DT < 150 ms. Haemodynamic manipulationsuch as the Valsalva maneuver will distinguishbetween severe irreversible diastolic dysfunction(grade IV) from less severe reversible (grade III)disease.

The pulmonary vein has a systolic (S wave), a

diastolic (D wave) and an atrial reversal (Arev

ration of 10.17 (p < 0.001 95% CI 3.2831.00) forR

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MAHARAJ 105DIASTOLIC DYSFUNCTION AND HEART FAILUREwave) component (Fig. 2). These waves are reci-procal to the left atrial waves. The S wave can bedivided into S1 and S2. The S1 occurs during LApressure a to c and c to x descent, andthe S2 occurs during LA pressure increase be-tween the x pressure nadir and the v pres-sure peak [94,95]. The D wave correlates with themitral E wave velocity. The Arev is determinedby atrial and ventricular compliance and atrialcontractility. The isovolumic relaxation time(IVRT) is the time interval between the aorticvalve closure and mitral valve opening. The IVRTis normally 7090 ms and is influenced by heartrate and loading conditions. Trends may be morehelpful than absolute values.

The mitral inflow propagation velocity (Vp) ismeasured using colour M-Mode. This providesvelocity information along a scan line that extendsfrom the mitral valve to the LV apex.

Refinements in echocardiography technologyinclude Tissue Doppler Imaging (TDI), colourTDI, strain and strain rate and have become animportant part of clinical practice [96].

Conventional echocardiography filters out lowvelocity, high amplitude signals and derives thevelocity and flow of blood by measuring theDoppler shifted frequency of the low amplitude,high frequency signal returning from blood flow.TDI excludes the signal from blood flow andinterrogates the signal from myocardial tissue.Three waveforms are noted- S (systolic), Ea (earlydiastolic), and Aa (late diastolic). Colour TDImeasures the mean velocities whereas pulsewave Doppler measure peak velocities in thesample volume [9699]. TDI has two importantlimitations. Firstly, the measured velocities aredependent on the angle of insonation. SecondlyTDI is of limited utility in analyzing regional wallmotion abnormalities as TDI cannot differentiateactively contracting myocardium from infarctedmyocardium that is tethering. Strain and strainrate is derived from colour TDI. Strain is themeasure of myocardial deformation and is thechange of length (L) of a myocardial segment ref-erenced to its original length (L0) as given by theequation E = L L0/L0 [100]. If both LO and L areknown then this referred to Lagrangian strain.Natural strain refers to when the L is referencednot to the original length but to the length at thepreceding time interval [101]. TDE measures nat-ural strain and magnetic resonance imaging mea-sures Lagrangian strain. Strain rate is the rate ofmyocardial deformation and is expressed aschange of strain per unit time. A more recent

innovation to strain analysis is speckle tracking5 year mortality [112]. This observation has beenconfirmed by other reports [9113]. Wang et al. per-formed one of the earliest studies evaluating therelationship between TDI-derived mitral annularvelocities and outcome [114]. A total of 518 pa-tients were recruited for this study (353 with car-diac disease and 165 normal subjects) with theendpoint of mortality at 2 years. This study foundthat if the Ea or S peak velocities were between 3and 5 cm/s then the hazard ratio for death was[102]. This involves a computer algorithm usingroutine greyscale imaging that contain uniquespeckle patterns. Within a user-defined area onthe myocardial wall, the image processing algo-rithm to track frame by frame changes in thespeckle pattern to velocity vectors [103]. Theseadvances have well described in recent publica-tions and are beyond the scope of this review[89,93,96,102].

Prognosis

There is a clear association between diastolicHF, asymptomatic diastolic dysfunction, and mor-tality that is influenced by several variables,including the population being studied, thethreshold EF used to define DHF and the influ-ence of co-morbidities. Several variables havebeen identified as independent clinical predictorsof mortality in patients with HF. These includeage, New York Heart Association Class IV symp-toms, CAD, Diabetes, peripheral vascular diseaseand the presence of valvular heart disease.Whether patients survive longer after a diagnosisof systolic HF than a diagnosis of systolic HF is stilldebated [104109] (Table 2). Hospital readmissionrates and length of hospital stay for patients withHFpreEF are similar to SHF and the former havea higher likelihood of functional limitations or la-bile symptoms on follow-up [110,111]. When out-come from HF is adjusted for the contribution ofco-morbidity, there is a uniformly poor prognosisregardless of the ejection fraction.

Information regarding the prognosis in asymp-tomatic diastolic dysfunction is sparse. A commu-nity based study of 2042 patients 45 years andolder found that patients with diastolic dysfunc-tion without a history of cardiac failure have a sig-nificant risk of death [112]. Compared with normaldiastolic function, those with mild diastolic dys-function have a hazard ratio of 8.31 (p < 0.001,95% CI 3.0023.10) and those patients with moder-ate to severe diastolic dysfunction have a hazard12.8 (95% CI 2.956) [114].

and colleagues found 43% of patients to have iso-

fall in early diastolic LV pressure [129]. In patients

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J Saudi Heart Assoc2012;24:99121Anaesthetic implications

Pre-operative assessment

The American College of Cardiology and theAmerican Heart association (ACC/AHA) as wellas the European Society of Cardiology andEuropean Society of Anesthesiology (ESC/ESA)guidelines recommend the use of risk indices forpre-operative cardiac evaluation for non-cardiacsurgery [115,116]. The Goldman, Detsky and Re-vised Cardiac Risk Index (RCRI) all identify HFas a predictor of perioperative cardiovascularevents [117119]. A limitation of these risk indicesis that they do not account for the patient withdecompensated HF who improves both symptom-atically and functionally on medical therapy.When this patient presents for elective surgeryseveral months later, the patients perioperativerisk calculated by the original Goldman Index doesnot appreciate the history of HFHF and the RCRIdoes not appreciate the patients clinical improve-ment. There is no specific risk model for predictingperioperative risk in patients with HfpreEF.

When planning surgical procedures in patientswith stable HF, it is important to identify those pa-tients that are unlikely to survive long enough toaccrue benefit from the procedure. Data from stud-ies describing the clinical profile of cardiac trans-plant patients have highlighted the difficulties inpredicting survival in patients with advanced HF.Several prognostic models have been developedto identify those patients with advanced HF witha high risk of death needing urgent transplanta-tion. These include the Heart Failure SurvivalScore (HFSS), the Seattle Heart Failure Model[120], and more recently the MUSIC Risk Score[121,122]. None of these scores were specifically in-tended for pre-operative risk stratification, butmay offer some guidance in making difficult deci-sions in patients with HF that may require surgery.

There is limited data on perioperative risk strat-ification for isolated diastolic dysfunction. Patientsrequiring vascular surgery have been shown tofrequently have asymptomatic isolated diastolicdysfunction that is associated with a significantlyhigher rate of major adverse cardiovascular events(MACE). The study by Flu and colleagues foundabout 50% of vascular surgical patients to haveisolated diastolic dysfunction and 80% of these pa-tients were asymptomatic. The study found an OR2.3 (95% CI 1.43.6) for 30 day MACE in all pa-tients with diastolic dysfunction compared withno ventricular abnormalities, abnormalities. The

OR for MACE in symptomatic HF was 1.8 (95%CI 1.12.9). This study highlights the importancewith diastolic dysfunction this compensatorymechanism fails [129]. These patients are unableto augment their cardiac output by increasingtheir end diastolic volume. Left ventricular enddiastolic pressure and pulmonary venous pres-sure rises, reducing the pulmonary complianceand increasing the work of breathing [129].

Patients with diastolic dysfunction have an asso-ciated reduction in chronotropic, vasodilator andcardiac output reserve compared with patientswithout diastolic dysfunction [123,130]. It is thoughtthat these factors may also contribute significantlyto the observed limitations in functional capacity.

Implications in the perioperative period

Asymptomatic diastolic dysfunction is fre-quently underappreciated in the elderly surgicallated diastolic dysfunction and a strong associa-tion in these patients with a prolonged length ofstay and higher rates of post-operative HF. Inter-estingly the study did not find an association withperioperative outcomes and systolic dysfunction.The association was between isolated diastolicdysfunction and perioperative MACE in cardiacsurgical patients. Isolated diastolic dysfunctionhas been shown to increase the risk for postoper-ative atrial fibrillation in cardiac surgical patients[123]. These observations make a compelling casefor the routine assessment of peroperative dia-stolic function.

Exercise capacity and diastolic dysfunction

Exercise capacity is a useful pre-operativescreening test. A self-reported limitation in exer-cise capacity has a negative predictive value of95% and a positive predictive value of about 10%for a major perioperative cardiovascular event[124,125]. Exercise intolerance is often the earliestclinical presentation of diastolic dysfunction andis a major determinant of quality of life [126].

Recent evidence suggests diastolic dysfunctionmay impair the Starling mechanism during exer-cise [127,128]. The tachycardia that occurs duringexercise reduces ventricular filling time. Inhealthy individuals ventricular filling is main-tained by progressive acceleration of the IVRTand an increased suction effect by a more rapidof looking beyond HF symptoms and advocatesfor the use of echocardiography in patients under-going high-risk surgery. A similar study by Matyalpopulation. Phillip et al. conducted a prospective

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MAHARAJ 107DIASTOLIC DYSFUNCTION AND HEART FAILUREstudy of 251 patients with at least one risk factorfor cardiac disease determining the prevalence ofdiastolic dysfunction in the geriatric surgical pa-tient. [131]. The mean age of the patients was72 7 years and diastolic filling abnormalitieswere discovered in 61.5% of the patients. A majorlimitation of this study was that no outcome mea-surement was performed so the clinical signifi-cance of the findings was not established.Similarly observations have been reported in pa-tients undergoing elective vascular surgery [132].It is highly likely that elderly patients with vascu-lar disease or hypertension would have some de-gree of diastolic dysfunction.

Induction of anaesthesia results in significantalterations in ventricular filling in patients withdiastolic dysfunction [133]. This may be due topositive pressure ventilation, reduced venousreturn and reduced right atrial contractility. Inpatients having aortic surgery, application ofthe aortic cross clamp worsens diastolic perfor-mance that returns to baseline upon release ofthe cross clamp [134]. In patients requiring car-diac surgery, diastolic dysfunction has beenshown to be a better predictor of haemody-namic instability than systolic dysfunction[135,136]. Moderate and severe diastolic dys-function is also independently associated withdifficulties with separation from cardiopulmo-nary bypass [135,137]. Pre-operative diastolicdysfunction is associated with a range of ad-verse outcomes including higher mortality,worse mitral regurgitation and longer hospitalstay in patients requiring surgical ventricularrestoration, mitral valve annuloplasty or electivevascular surgery [132,138,139].

Perioperative atrial fibrillation in patients withdiastolic dysfunction results in a significant reduc-tion in left ventricular filling and cardiac outputdue to loss of atrial kick. Atrial fibrillation maybe precipitated by hypovolaemia, hypervolaemiawith atrial overdistension, electrolyte abnormali-ties, particularly hyper and hypokalaemia, anae-mia, abrupt withdrawal of beta-blockers orcalcium channel blockers, and ischaemia. The on-set of atrial fibrillation has been shown to precip-itate HF in patients with pre-existing diastolicdysfunction [140]. The presence of pre-operativediastolic dysfunction is a strong independentpredictor for developing post-operative atrialfibrillation after cardiac surgery [141]. Diastolicdysfunction also predicts long term rhythm afterintraoperative ablation for atrial fibrillation [142].The dominant mechanism is probably inflamma-

tory mediated though the exact etiology for thedevelopment of atrial fibrillation in these patientsis unknown. This may explain the observation thatstatins may reduce the rate of atrial fibrillationafter cardiac surgery [143].

Myocardial ischaemia results in significantimpairment in LV relaxation and increases therisk of rhythm disturbances as already discussed.The earliest abnormality induced by epicardialocclusion is a reduced ventricular compliance.This precedes regional wall motion abnormalities,electrocardiographic changes or chest pain [144].There are two mechanism by which acute myocar-dial ischaemia induces diastolic dysfunction [145]The first mechanism is by arterial hypoxaemiaand occurs within 2 min, The second mechanismis by perfusion ischaemia and occurs at about2030 min. Diastolic dysfunction is commonlyassociated with LVH. Increases in intra-cavitarypressure together with increased left ventricularmass result in malperfusion of the left ventricle.LVH may be eccentric or concentric. Each geomet-ric pattern is associated with a particular pressureor volume stimuli, contractile efficiency and prog-nosis. The concentric pattern carries the worseprognosis compared with eccentric hypertrophy[146]. In patients with right HF, increased rightatrial pressure impairs postcapillary blood flowresulting in coronary venous engorgement [33].Right ventricular dilatation may also impede LVfilling by ventricular interdependence.

There is limited clinical data on the effect ofanaesthetic drugs on diastolic function. The choiceof anaesthetic technique has been shown to influ-ence diastolic properties in patients with pre-existing diastolic dysfunction [91,147]. In a smallrandomised study of 24 patients, the use of sevo-flurane during spontaneous ventilation preservedearly diastolic function better than propofol. How-ever during a balanced anaesthetic technique withpositive pressure ventilation, no difference be-tween sevoflurane and propofol on diastolic func-tion was observed [91]. These findings areconsistent with other studies [147]. The mecha-nism by which propofol affects diastolic functionare similar to volatile anaesthesia [148,149]. Thereis impaired calcium reuptake by the sarcoplasmicreticulum and modulation of phosphorylation ofthe contractile proteins [150]. More recently acomparisons between isoflurane, desflurane andsevoflurane found no significant effect on diastolicperformance in healthy subjects and no differencebetween these agents in patients with diastolicdysfunction [151]. Morphine and midazolam donot appear to have any effect on diastolic perfor-

mance [152,153]. Similarly, remifentanil has been

cance of the study is unclear as there was a statis-

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J Saudi Heart Assoc2012;24:99121tically significant difference in the heart ratebetween the control group and the sepsis group(116 15 beat/min septic shock, 110 26 beat/shown to not to impair diastolic function inhealthy volunteers [154].

Diastolic dysfunction and sepsis

The occurrence of myocardial dysfunction in pa-tients with sepsis carries a significant burden ofmortality (70%) compared with those patients thatdo not have myocardial dysfunction [155]. Bothsystolic and diastolic dysfunction have been de-scribed. Parker et al. demonstrated the relation-ship between diastolic dysfunction and sepsis in1984 [156] comparing haemodynamic and radio-nuclide cineangiographic data between a groupof 20 patients with septic shock and a controlgroup of 32 critically ill patients with negativeblood cultures, not in shock. The patents with sep-tic shock were volume resuscitated to a PAWP of1215 mmHg and inotropes were added as re-quired. Survivors of septic shock (n = 13) had highleft ventricular volumes (mean left ventricular enddiastolic volume index (LVEVPI) 159 29 mL/m2)that returned to normal by about 10 days. Non-survivors had normal mean LV volumes (meanLVEDVI 81 9 mL/m2) that did not change duringthe 10 day period. Unfortunately, no ventricularvolume data was reported for the control group.The same group of investigators evaluated 39 pa-tients with septic shock again using haemody-namic and radionuclide angiographic studies[157]. Survivors (n = 22) displayed simultaneousbiventricular dilatation that returned to normalafter recovery. Non-survivors (n = 17) displayedless severe dilatation but did not improve on sub-sequent evaluation. Changes in right ventricularvolumes paralleled changes in the left ventricle[157].

Using both haemodynamic and radionuclidemeasurements, in a group of 56 patients admittedto ICU, Ognibene et al. was able to show higherPAWP with a trend towards higher LVEDVI in pa-tients with septic shock compared with controls[158]. The pre-enrollment fluid resuscitation inthe septic shock group was more aggressive thanthe controls making the data difficult to interpret.

More recent studies have used echocardiogra-phy to evaluate diastolic performance. Jafri et al.observed that Doppler parameters of LV fillingwere abnormal in a subset of 46 septic patientswith or without shock [159]. The clinical signifi-min, sepsis without shock vs. 73 12 beat/mincontrols, p < 0.05) and the echocardiographymodality used does not account for patients withpseudonormal filling pattern. Subsequently, Muntet al., have demonstrated similar abnormalities indiastolic performance in a group of 24 critically illpatients [160]. This report also identified abnor-malities of LV filling as being independently pre-dictive of mortality [160]. Non-survivors ofsevere sepsis had more abnormal Doppler param-eters of diastolic relaxation, as measured by E/VTIand deceleration time (DT). In a multivariate anal-ysis, DT was the only echocardiographic parame-ter that independently predicted mortality. Allpatients were studied within 24 h of presentationand after volume resuscitation. There was nodifference in mean pulmonary artery occlusionpressure or heart rate between survivors andnon-survivors. This study has several limitationsthat deserve comment. Although patients withpre-existing cardiac disease were excluded, therewas no control group and systolic function wasnot assessed making it difficult to draw meaning-ful conclusions. Mortality was significantly associ-ated with advanced age and also with abnormalDoppler parameters of diastolic relaxation. It isimpossible to determine whether sepsis inducedan abnormality of LV relaxation in non-survivors,or whether there was pre-existing diastolicdysfunction in this subgroup of patients. Interest-ingly, cardiac output was actually higher in non-survivors than in survivors in this study [160].

Baitugaeva et al. examined diastolic perfor-mance in 59 patients between the ages of 1824 years with sepsis, severe sepsis and septicshock and noted a significant relationship be-tween diastolic dysfunction and pro-inflammatorycytokines [161]. The patients in this age group areunlikely to have pre-existing diastolic dysfunction.The findings in these studies are consistent with agrowing body of evidence from experimentalstudies that supports the concept of sepsis orendotoxin induced abnormalities in LV compli-ance [162,163]. The majority of these studies haveshown a reduction of ventricular compliance bypressurevolume analysis early (within hours)into the course of sepsis without ventricular dila-tion. Over a period of days and with the adminis-tration of intravascular volume, the left ventricledilates. Measured compliance at this stage maystill be reduced, or may return toward normal,and it has been proposed that ventricular compli-ance in sepsis may be volume dependent [2]. It isestimated that about 20% of patients with septicshock will have some impairment of left ventricu-

lar relaxation [164]. The spectrum of cardiac

exercise tolerance and even HF [177]. This makes

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MAHARAJ 109DIASTOLIC DYSFUNCTION AND HEART FAILUREstolic dysfunction in the pediatric patient. Datafrom 238 healthy neonates suggests that at birththere is impaired left ventricular relaxation char-acterized by a prolonged isovolumic relaxationtime and limited early diastolic filling predomi-nantly dependant on atrial contraction [168]. Inthe first week of life there are improvements in leftventricular relaxation. By two months of age thepattern of transmitral flow changes dramaticallywith early mitral flow velocities increasing byabout 80% from newborn values [168,169]. The ef-fect of heart rate on early filling appears to be neg-ligible and does not account for the observeddifferences [168]. In contrast, during the same per-iod, there are no significant improvements in tri-cuspid diastolic annular motion or inflowvelocities, implying that the right ventricle has de-layed improvement in diastolic function [169]. Inpre-term infants the maturation of diastolic func-tion is prolonged and at two months there is stilla predominance of diastolic filling during atrialcontraction [170]. The maturational process of dia-stolic performance takes about three months andlimits tolerance to preload stressors [171]. A studyof cardiac growth in healthy children using TDIabnormalities ranges from isolated diastolicabnormalities to HFpreEF and systolic HF.

Ventricular dilation seen in early studies in bothhuman and animal studies has been implicated inthe maintenance of cardiac output in the face ofimpaired contractility [165].

Animal models have confirmed both systolicand diastolic dysexplored the differential abilityof inotropes to restore diastolic function[166,167]. Dobutamine improved systolic functionbut did not improve diastolic dysfunction in ani-mal models of sepsis.

There are several confounding issues that makeevaluation of diastolic performance in critical ill-ness particularly challenging. These include thepotential effects of inotropes, volume resuscitationand the lack of well-established reference rangesfor diastolic parameters in critical illness. It ishoped that the use of more standardised methodsfor evaluating diastolic function such as TDI andstrain rate will overcome some of these difficultiesand provide insight into the interrelation of sepsisand ventricular diastolic function and its implica-tions for patient survival.

Pediatric patients with cardiac disease

It is important to understand the maturation ofdiastolic function before we can appreciate dia-showed a correlation between diastolic functionand age [172].a convincing case for early closure of ASD [178].Following repair of a patient with Tetralogy of

Fallot (TOF), several acute and chronic complica-tions have been shown to have a significant im-pact on the post-operative course. In thesepatients, biventricular systolic function is usuallywell preserved with restrictive right ventricularphysiology [179]. Right ventricular restriction ischaracterised by anterograde diastolic pulmonaryflow, implying that the right ventricle has becomea stiff conduit in late diastole [180185]. Restrictivefilling following repair of a TOF is associated withincreased inotropic requirements, prolongedmechanical ventilation time, higher doses ofdiuretics and longer hospital stay as well as poorexercise capacity and symptomatic arrhythmias[182]. Recent studies using TDI and strain rateand strain, after complete repair of TOF, havefound significant systolic and diastolic dysfunc-tion of the right ventricle. These patients have asignificant risk of late right ventricular failure,and pulmonary insufficiency [183185]. TDI andstrain rate may provide invaluable informationabout the need for pulmonary valve replacement.These reports provide further evidence that com-plete repair of TOF should be performed duringinfancy as delayed repair exposes the myocar-dium to chronic hypoxaemia and hypertrophy[186,187].

Diastolic dysfunction and medical disease

Renal diseaseThere appears to be a consistent relationship be-

tween diastolic dysfunction and chronic renal dis-ease in both paediatric and adult patients [188].There are two parallel pathophysiological mecha-nisms that underlie the development of diastolicdysfunction in patients with chronic renal insuffi-ciency [188]. The first is that cardiac remodelingresults in left ventricular hypertrophy (LVH).In children with congenital heart disease, dia-stolic dysfunction has historically been under-recognised. The use of transcatheter techniqueshave advanced the understanding of diastolic dys-function in children. TDI and strain rate and strainimaging studies have revealed no significant in-crease in left sided pressure after closure of an at-rial septal defect (ASD) [173176]. In contrast, ASDclosure in adult patients is characterised by an in-crease in left ventricular dimensions, elevations inN-terminal proBNP, delayed improvement inPressure overload results in concentric LVHwhereas eccentric LVH may be related to volume

pensity-matched study of patients in the Digoxin

induced by both type 1 and type 2 diabetes are

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J Saudi Heart Assoc2012;24:99121Investigation Group (DIG) trial to determine theimpact of LVEF, chronic renal insufficiency (CRI)and mortality in a cohort of 7788 ambulatory pa-tients in sinus rhythm [195]. DHF was present in988 patients (defined as LVEF > 45%). Interest-ingly, this study concluded that mortality associ-ated with chronic renal insufficiency (CRI) washigher in patients with diastolic HF comparedwith SHF [195,196]. Additionally, there was agraded relationship with higher CRI-associatedmortality occurring with increasing LVEF. Thereare several potential explanations for this observa-tion. The mean age of patients with DHF was3 years older than patients with systolic HF(P < 0.0001) and there were more patients>75 years of age with CRI and DHF than systolicHF. Renal impairment in DHF may representintrinsic renal disease in advanced age. Thirdly,the influence of medical therapies needs to be ex-plored. Patients with DHF do not show the sameprognostic improvement when commenced onmedical therapy when compared with matchedpatients with HF and low EF [197]. Lastly, theremay be unmeasured co-variables that may ac-count for these observations.

Diabetes

Although diabetes is a well recognized risk fac-tor for the acceleration of ischaemic heart diseaseand hypertension, the relationship between dia-betes and cardiac disease independent of thesediseases is less well understood. Diabetic patientswithout significant coronary artery disease maydevelop features of abnormal LV relaxation withnormal systolic function [198201]. The severityof the diastolic dysfunction correlates indepen-dently with the derangement in glycaemic controlas manifested by elevated glycosylated haemoglo-bin [199201]. A nationwide case control studyoverload. Over a period of time, the maladapta-tion phase of LVH results in decreased capillarydensity, coronary reserve and subendocardial per-fusion. Myocardial fibrosis with systolic and dia-stolic dysfunction result.

The second mechanism involves vascular injury.Chronic renal disease and cardiac disease sharemany common risk factors. These include athero-sclerosis and vascular calcification.

Chronic renal dysfunction is frequently associ-ated with diastolic HF and has been shown toindependently increase mortality [189194].Ahmed and colleagues conducted a post hoc pro-showed that diabetes was independently associ-ated with idiopathic cardiomyopathy [202]. Thesimilar [216218].

Chronic obstructive airways disease (COPD)The cardiovascular consequences of COPD in-

clude impaired left ventricular filling, arterial stiff-ness, cor pulmonale and chronic HF [219]. TheMulti Ethnic Study of Atherosclerosis (MESA)Lung is a population based study that exploredthe relationship between emphysema, airflowobstruction and left ventricular filling in 2816 sub-jects [220]. Magnetic resonance imaging was usedto measure left ventricular structure and function,CT scanning was used to define the severity ofemphysema and spirometry was performedaccording to the American Thoracic Society guide-lines. The study found a linear relationship be-tween both severity of emphysema and airflowobstruction with impairment of left ventricularfilling, reduced stroke volume and cardiac outputwithout significant reductions in ejection fraction.These findings are consistent with other workwhich has highlighted the presence of both rightand left ventricular diastolic dysfunction early inthe course of COPD, without overt cardiovasculardisease [221]. The mechanisms by which COPDcauses impaired left ventricular filling includepulmonary vascular changes, pulmonary hyperin-pathophysiological mechanisms that underly therelationship between diabetes and diastolic dys-function are probably mediated through themicrocirculation. Intra vascular ultrasound studieshave shown impaired coronary flow reserve inboth type 1 and type 2 diabetic patients [203,204].A reduced coronary flow reserve indicates coro-nary microvascular dysfunction, in the absenceof epicardial coronary stenosis [205]. This micro-vascular dysfunction may lead to myocardial cellinjury, fibrosis or apoptosis [206]. Other possiblemechanisms of microcirculatory dysfunction in-clude autonomic dysfunction, endothelial dys-function and insulin resistance [207209]. Thecellular mechanisms that underly diabetic dia-stolic dysfunction are probably due to three char-acteristic metabolic abnormalities that areobserved in diabetes [201]. These are (1) hyper-glycaemia which generates reactive oxygen spe-cies causing mitochondrial dysfunction (2.)hyperinsulinaemia which promotes myocytehypertrophy and (3) elevations in non-esterifiedfatty acids which are thought to induce insulinresistance and myocardial apoptosis [210215].The clinical features of the cardiovascular changesflation, arteriolar hypoxia and ventricular interde-pendence. Other less well understood

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Table 4. Summary of intravenous therapy for a hypertensive crisis [240,241].

Drug Class Dose Comments

Clevidipine Third generation dihydropyridineCCB

Starting dose 12 mg/h, doubledevery 90 min until target BP reached.No more than an average of 21 mg/hrover a 24 h peiod

Specifically arteriole dilator. Rapidonset 24 min. Agent containsphospholipids that support microbialgrowth and vial must be changedevery 4 h

Enalaprilat ACE inhibitor 1.25 mg every 6 h over a 5 min period.50% dose reduction for patients withcreatinine clearance 2.0 lg/kg/min

Concern about cyanide, toxicity andmeth-haemaglobinaemia

CCB = calcium channel blocker, ACE = angiotensin-converting enzyme, ICP = intracranial pressure.

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load and afterload. LVEF is usually derived by ra-

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J Saudi Heart Assoc2012;24:99121mechanisms involve systemic inflammation, oxi-dative stress, connective tissue degradation andvascular dysfunction. Retrospective pharmaco-epidemiologic studies have hinted at the possiblebenefit of statins combined with low dose inhaledcorticosteroids at reducing the acute coronaryevents and hospitalizations in patients with COPD[222224]. Randomized control trials are awaited.

Cirrhotic cardiomyopathyThe cardiac dysfunction noted in patients with

liver cirrhosis is greater than what is accountedfor based on alcohol alone and has been termedcirrhotic cardiomyopathy [225]. The term refersto spectrum of cardiac abnormalities that includesystolic and diastolic dysfunction, electrophysio-logical changes such as prolonged QT intervaland a diminished response to catecholamines.The mechanism by which cirrhosis causes dia-stolic dysfunction is a combination of myocardialhypertrophy, fibrosis and sub-endothelial oedema[226]. Increased sodium intake may induce myo-cardial hypertrophy and may in itself be responsi-ble for some of the diastolic dysfunction observedin these patients [227]. The severity of diastolicdysfunction observed is more pronounced in pa-tients with ascites. This may be a consequence ofthe mechanical effects of ascites or reflect theseverity of liver cirrhosis [228]. Patients with dia-stolic dysfunction are very sensitive to the volumechanges that occur with transjugular intrahepaticportosystemic shunts (TIPS) procedures [229].Portal decompression by TIPS results in rapidshifts of larges blood volumes from the splanchniccirculation to the heart. The persistence of dia-stolic dysfunction after TIPS has been found tobe a strong independent predictor of mortality[229]. Diastolic dysfunction has been associatedwith a slower mobilisation of ascites [230]. Livertransplantation improves/reverses diastolic dys-function though the evidence is sparse [231]. Thetime course for the changes that occur after trans-plantation are not completely understood. Someauthors have reported a persistence of hyperdy-namic circulation for up to two years after trans-plantation and others report an immediateamelioration to the cardiac and circulatorydisturbance.

Is diastolic heart failure a precursor to theevolution of systolic heart failure or a syndrome onits own?

Whether HF is a single syndrome with HFpreEF

preceding HF with systolic impairment or whetherHF is two distinct syndromes: one with concentricdial measurements of the LV. During the earlyperiod of systolic dysfunction, there may be radialcompensation for longitudinal impairment andthis does not reflect changes in regional and tem-poral abnormalities in cardiac muscle[232,233,235]. In this context, a normal ejectionfraction does not equate with preserved systolicfunction. If myocardial performance is viewed asa muscle pump then indices of longitudinal func-tion and non-uniformity define ventricular perfor-mance [55,232235]. These include TDI derivedmitral annular velocity and strain and strain rateand may reveal significant systolic impairment inthe face of a normal ejection fraction. Diastolicand systolic HF may represent different pheno-types of the same pathophysiological process[55,232,233,235]. Proponents of the single-syn-drome hypothesis suggest there is a progressionof disease from HfpreEF to HF with systolicimpairment and that the decline in systolic func-tion may be better appreciated by tissue Dopplerindices than by LVEF [232,233,235]. Advocates forthe two-syndrome model cite the lack of prognos-tic improvement in recent therapeutic trials withDHF as compared to the success in SHF. Thiswould imply different disease processes. Thepresence of ultrastructural changes in the cardiacmyocyte, and changes in matrix metalloproteinasealso support the latter view [236238].

TreatmentThe key targets for therapy are active relaxation,

passive LV relaxation and myocardial fibrosis[239]. The management of acute decompensateddiastolic HF should focus on correcting the precip-itating factors such as myocardial ischaemia,hypertensive crisis, acute rhythm disturbances,hyperglycaemia and hyperinflation as well astherapy to relieve pulmonary congestion. Thesteep gradient of the diastolic pressurevolumerelationship means that a small change in aremodeling and diastolic dysfunction (DHF) andthe other with eccentric remodeling and systolic-diastolic dysfunction (SHF) is unclear.

The evolution of our understanding of ventricu-lar function had led to various models of cardio-vascular performance each with its own set ofdefining variables. If the myocardial performanceis defined as a haemodynamic pump then LVEF isan important measure [55,218,232234]. The hae-modyamic performance of the heart is influencedby factors outside the myocardium, such as pre-LVEDV results in a significant change in LVEDP,diuretics or nitrates should therefore be carefully

both groups norepinephrine was use to maintainmean arterial pressure. There were significant

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MAHARAJ 113DIASTOLIC DYSFUNCTION AND HEART FAILUREconsidered when attempting to reduce LVEDV.Hypertensive crisis are frequently encounteredin these patients. There have been several excitingdevelopments in the pharmacotherapy availableand the choice should be based on individual pa-tient characteristics (Table 4) [240,241]. The use ofnon-invasive ventilation is an effective therapy foracute exacerbations of diastolic HF reducing hos-pital mortality and the need for endotracheal intu-bation [242,243]. Less recognized factors may alsoplay a role. For example obesity is a surrogatefor obstructive sleep apnoea (OSA). The cardio-vascular abnormalities associated with OSA in-clude LV hypertension, paroxysmal atrialfibrillation and sympathetic activation. NIV willreverse these abnormalities [244].

Beta blockers have been proposed for the treat-ment of HFPreEF based on the assumption thatthe rate lowering effect of prolonging diastolewould result in better LV filling [6]. There is datafrom observational studies suggesting a differen-tial benefit for beta blockers in HFPreEF comparedwith patients with systolic impairment [245,246].The sinus node If blocker Ivabradine offers the po-tential to reduce heart rate without any effect oncontractility and may find a niche in patients withHFPreEF [247]. Aldosterone is known to promoteventricular fibrosis and collagen deposition. Thealdosterone antagonist spironolactone has beenshown to limit myocardial fibrosis [248]. Canre-none is a spironolactone metabolite. In a smallrandomized study, canrenone improved LV dia-stolic performance without altering blood pres-sure of LV mass significantly [249]. The trialsevaluating angiotensin receptor blockers cande-sartan (CHARM PRESERVED trial), ibesartan (I-PRESERVED trial), and the angiotensin-convert-ing enzyme inhibitor peridopril (PEP CHF trial)did not show any survival benefit when comparedwith placebo [250252].

The management of circulatory failure related todiastolic dysfunction in critical illness is largelysupportive. Adequate fluid resuscitation is oftenfollowed by drugs with a positive lusitropic effect.In practice systolic and diastolic dysfunction oftenco-exist and phosphodiesterase inhibitors and cal-cium channel sensitisers are invaluable. Levosim-endan is a calcium-sensitizing agent that mediateseffect through binding to Troponin C. This resultsin increased myocardial contractility with minimalincreases in oxygen consumption. In this study,levosimendan improved both systolic and dia-stolic function in LPS treated animals and con-trols. Levosimendan detaches from troponin C at

low calcium concentrations so its effect on diastoleimprovements in cardiovascular performanceand organ function in the levosimendan group(end-diastolic and end-systolic volume index andleft ventricular stroke work index) The second trialinvolved thirty-five patients with septic shock,ARDS and right ventricular failure [254]. Magneticresonance imaging showed an improved rightventricular end diastolic volume index as well asan improved right ventricular end systolic volumeindex and right ventricular ejection fraction. Thesewere small studies not powered to show any mor-tality benefit and there is insufficient evidence torecommend the routine use of levosimendan insepsis induced diastolic dysfunction. A meta-anal-ysis by Landoni et al. evaluated the role of levo-simendan in critically ill patients [256]. The studyconcluded a mortality benefit in favour of levosim-endan (OR 0.74, 95% CI 0.62089). This methodi-cally rigorous analysis pooled 27 studiesinvolving patients with decompensated HF, elec-tive cardiac surgery, acute myocardial infarctionand elective abdominal aortic aneurysm repair.The heterogeneity of patients included in thismeta-analysis makes it difficult to extrapolate itsfindings to severe sepsis.

Future trials should focus on the specific struc-tural and functional abnormalities that occur inHFPreEF patients. These include cardiomyocytehypertrophy, alterations in myocardial extracellu-lar matrix metabolism, the shift in myocyte metab-olism from glucose to free fatty acids, and thehigher expression and phosphorylation titin iso-forms [257].

Conclusion

Diastolic dysfunction and HF remain underap-preciated in the peri-operative and critical careenvironment. Epidemiological data predict thatdiastolic HF will become the more frequentlyencountered type of HF encountered in clinicalpractice. Advances in echocardiography technol-ogy have been instrumental in our understandingis unexpected. It is probable that Toponin C mayhave some effect on Troponin I even duringhyperphosphorylation [166]. The use of levosi-mendin septic shock was first described in 2005and since then there have been two randomisedclinical trials in this group of patients [253255].The first trial compared levosimendan with dobu-tamine in 28 patients with septic shock [255]. Inof ventricular function. Currently, therapeutic

1999;33:194855.

ventricular systolic function; epidemiology, clinicalcharacteristics, and prognosis. J Am Coll Cardiol

of left ventricular diastolic function by echocardiography.

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J Saudi Heart Assoc2012;24:991212004;43:31727.[11] Thomas MD, Fox KF, Coats AJ, Sutton GC. The

epidemiological enigma of HF with preserved systolicfunction. Eur J Heart Fail 2004;6:12536.

[12] Owan TE, Redfield MM. Epidemiology of diastolic HF.Prog Cardiovasc Dis 2005;47:32032.

[13] Ergina PL, Gold SL, Meakins JL. Perioperative care of theelderly patient. World J Surg 1993;17:1928.

[14] Kessler KM. Diastolic HF. Diagnosis and management.[9] Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J,Kitzman D. Predictive value of systolic and diastolicfunction for incident congestive HF in the elderly: thecardiovascular health study. J Am Coll Cardiol2001;37:10428.

[10] Hogg K, Swedberg K, McMurray J. HF with preserved leftoptions specific to this group of patients is limitedand mortality has remained unchanged. In con-trast to patients with reduced EF, the prognosisfor those with HTPreEF has failed to improve inthe last three decades. The potential public healthburden should make diastolic dysfunction anddiastolic HF a priority.

Conflict of interest

The authors have no conflicts of interest todeclare.

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