review article similarities and differences between the … · 2019. 7. 31. · to diastolic heart...

Hindawi Publishing CorporationCardiology Research and PracticeVolume 2013 Article ID 824135 6 pageshttpdxdoiorg1011552013824135

Review ArticleSimilarities and Differences between the Pathogenesis andPathophysiology of Diastolic and Systolic Heart Failure

Kazuo Komamura

Cardiovascular Division Hyogo College of Medicine 1-1 Mukogawa-cho Nishinomiya Hyogo 663-8501 Japan

Correspondence should be addressed to Kazuo Komamura komamurahyo-medacjp

Received 19 August 2013 Revised 8 October 2013 Accepted 10 October 2013

Academic Editor Dirk Westermann

Copyright copy 2013 Kazuo Komamura This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Pathophysiology of heart failure has been considered to be a damaged state of systolic function of the heart followed by a state of lowcardiac output that is systolic heart failure Even if systolic function is preserved left ventricular filling in diastole can be impededand resulted in elevation of filling pressure and symptoms of heart failure This kind of heart failure is called diastolic heart failureNowadays diastolic heart failure is referred to as heart failure with preserved ejection fraction (HFpEF) whereas systolic heartfailure is referred to as heart failure with reduced ejection fraction (HFrEF) In this paper the similarities and differences betweenthe pathogenesis and pathophysiology of diastolic and systolic heart failure were reviewed Although diastolic heart failure is acommon condition of heart failure worldwide its pathophysiology has not been sufficiently elucidated This is thought to be themost significant reason for a lack of established treatmentmethods for diastolic heart failureWe hope to proceedwith future studieson this topic

1 Introduction

Pathophysiology of heart failure has been considered to be adamaged state of systolic function of the heart followed by astate of low cardiac output (systolic heart failure) Howevereven if systolic function is preserved left ventricular fillingin diastole is impeded due to various factors This conditionleads to congestive heart failure due to the rise in left ventricu-lar end-diastolic pressure and the decrease in cardiac outputThis kind of pathophysiology is now known as diastolic heartfailure [1 2] In recent years diastolic heart failure causedby the affected left ventricle has become a clinical issue [3]Nowadays diastolic heart failure is referred to as heart failurewith preserved ejection fraction (HFpEF) whereas systolicheart failure is referred to as heart failure with reducedejection fraction (HFrEF)This is because evaluating accuratepathophysiology and diagnosis of diastolic heart failure is infact difficult

2 Diastolic Dysfunction

Diastole of the left ventricle is composed of isovolumic relax-ation and ventricular filling Relaxation of the left ventricle is

an active process that occurs as a result of energy-dependentuptake of intracellular calciumby the sarcoplasmic reticulumwhose concentration has risen during the systolic phase

Relaxation of the left ventricle is impaired in a diseasestate caused by energy metabolism disorders or calcium-handling abnormalities such as myocardial ischemia andmyocardial hypertrophy Left ventricular filling phase abnor-mality namely elevation of left ventricular stiffness influ-ences left ventricular flow dynamics during filling phase andis commonly caused by myocardial fibrosis or hypertrophy

When left ventricular diastolic function is impairedcardiac output is reduced because the left ventricle is not filledenough in diastole due to left ventricular inflow obstructionBy contrast to compensate for reduced cardiac outputincreasing the inflow pressure to the left ventricle (andconsequently left ventricular end-diastolic pressure) becomesnecessary which in turn increases left atrial pressure As aresult left ventricular dysfunction easily and directly causespulmonary congestion

The end-systolic pressure-volume relationship is thesame as a normal heart in diastolic heart failure but theend-diastolic pressure-volume relationship shifts upwards(Figure 1(a)) [3] As a result left ventricular end-diastolic

2 Cardiology Research and Practice

End-systolicpressure-volume

LV p

ress

ure

LV volume

Diastolic failure

End-diastolicpressure-volume

relationship

Normal

relationship = Emax

(a)

LV p

ress

ure

LV volume

Elevation of LV

End-diastolic pressure

(b)

Figure 1 (a) The end-systolic pressure-volume relationship is the same as a normal heart in diastolic heart failure but the end-diastolicpressure-volume relationship shifts upwards As a result left ventricular end-diastolic pressure rises (b) In pathologies with diastolicdysfunction when an abrupt increase in blood pressure occurs the pressure-volume loop shifts to the upper right without decrease in 119864maxTherefore pulmonary congestion is induced as a result of the significant increase in left ventricular end-diastolic pressure LV left ventricular

pressure rises In pathologies with diastolic dysfunctionwhen an abrupt increase in blood pressure occurs thepressure-volume loop shifts to the upper right withoutdecrease in 119864max (absolute index of contractibility) There-fore pulmonary congestion is induced as a result of thesignificant increase in left ventricular end-diastolic pressure(Figure 1(b))

By contrast in systolic dysfunction left ventricular con-tractile function decreases and 119864max gets smaller (Figure 2)Meanwhile the end-diastolic pressure-volume relationshipshifts downwards rather than remaining unchanged Tomaintain cardiac output the pressure-volume loop shiftsright due to increase in preloadTherefore the left ventricularpressure-volume loop operates on the steep part of the end-diastolic pressure-volume curve consequently causing end-diastolic pressure to rise

3 Are Diastolic Dysfunction and SystolicDysfunction Separate Diseases

In diastolic dysfunction contractility of whole left ventricleis considered normal However the contractile velocity insystole measured with tissue Doppler decreased in both sys-tolic and diastolic dysfunction [4] Furthermore local con-tractility in longitudinal direction is known to be impairedlocally in diastolic heart failure [5] Recent findings suggestthat contractility decreases even in diastolic heart failurein myocardium level By contrast diastolic function is alsoimpaired in systolic heart failure and has been shown todecrease exercise tolerance and be one of the determinantsof prognosis [6]Therefore diastolic and systolic heart failure

are not considered to be independent and separate entitiesThe single syndrome hypothesis of heart failure is thereforeadvocated (Figure 3) [1] In that hypothesis heart failure is asingle continuous disease spectrum and systolic and diastolicheart failure are phenotypes at two extremes

Thus there is the ldquogrey zonerdquo in diagnosing HFrEF withLVEF of 45 to 50 or 45 to 55 In other words some ofHFpEFwith LVEF of 45 to 55might be diagnosed as HFrEFrather than HFpEF As shown in Figure 3 a phenotype ofheart failure comprised of some extent of systolic dysfunctionand some extent of diastolic function Heart failure withLVEF of 45 to 55 would be located in the middle of thecontinuum of disease spectrum

By contrast some researchers have advocated that dias-tolic function is not something that should only be notedin the pathogenesis of diastolic heart failure but shouldbe widely viewed as a determinant of pathophysiology inheart failure [7] Heart dysfunction that occurs as a result ofheart disease causes diastolic dysfunction Among such casesthere exist patients with concurrent systolic dysfunctionFurthermore a portion of patients with heart dysfunctionclinically exhibit symptoms of heart failure Among themthose with significant systolic dysfunction where the mainpathology is systolic heart failure and diastolic dysfunctionare said to have diastolic heart failure

4 The Diagnostic Criteria for DiastolicHeart Failure

Definition of systolic heart failure is reduction of the leftventricular ejection fraction Thus its diagnosis is quite easyBy contrast diagnosis of diastolic heart failure is difficult

Cardiology Research and Practice 3

Decrease

NormalSystolic failure

LV p

ress

ure

LV volume

in Emax

Figure 2 In systolic dysfunction LV contractile function decreasesand 119864max gets smaller Meanwhile the end-diastolic pressure-volume relationship shifts downwards rather than remainingunchanged To maintain cardiac output the pressure-volume loopshifts right due to increase in preload Therefore the LV pressure-volume loop operates on the steep part of the end-diastolic pressure-volume curve consequently causing end-diastolic pressure to riseLV left ventricular

Diastolic heart failure Systolic heart failure

Systolic dysfunction

Diastolic dysfunction

LV hypertrophyMyocardial fibrosis

LV dilatationCardiomyocyte loss

High LowLeft ventricular ejection fraction

Figure 3 Diastolic and systolic heart failure are not consideredto be independent and separate entities Heart failure is a singlecontinuous disease spectrum and systolic and diastolic heart failureare phenotypes at two extremes

since there are no simple and reliable criteria Thereforediastolic heart failure can be clinically diagnosed whenclinical symptoms and findings of heart failure are exhibitedand decrease in left ventricular ejection fraction is none orminimal

The American College of Cardiology Foundation and theAmerican Heart Association define diastolic heart failure asa condition having the typical signs and symptoms of heartfailure with a normal left ventricular ejection fraction with-out valvular abnormalities on echocardiography [8] Vasanand Levy define diastolic heart failure as (1) exhibiting clinical

symptoms of congestive heart failure (2) having normal leftventricular systolic function during congestive heart failure(left ventricular ejection fraction of 45 to 50 and above) and(3) having left ventricular diastolic dysfunction Those thatmeet all these items and who have congestive heart failurethat is not caused by valvular heart disease cor pulmonaleor primary volume overload are considered as ldquodefinite dias-tolic heart failure (definite DHF)rdquo cases Currently accuratediagnosis of (3) needs cardiac catheterization which could beskipped in a common clinical situation

Diastolic heart failure is strongly suspected (probableDHF)when conditions (1) and (2) aremet [9]Whendiagnos-ing diastolic heart failure it is important to perform a carefulexclusion of valvular heart disease pericardial disease rightheart failure intracardiac tumor congenital heart diseaseand high-output cardiac failure Zile et al demonstratedthat diastolic functional abnormalities caused an increasein left ventricular filling pressure and clinical symptomsof congestive heart failure using cardiac catheterization forpatients with heart failure with preserved ejection fractionand patients with diastolic heart failure [10 11] The currentlyaccepted criteria for diagnosis of diastolic heart failure areessentially a clinical diagnosis Thus it is important tounderstand that there are possibilities that diastolic heartfailure means somewhat broader range than what diastolicheart failure exactly stands for

5 Diastolic Heart Failure from the Perspectiveof Clinical Features

According to reports by Owan et al and Bhatia et alroughly half of hospitalizations for heart failure are dueto diastolic heart failure [12 13] Compared with systolicheart failure diastolic heart failure is seen more often in theelderly and women and accompanied by hypertension andanemia Comorbidity rate of obesity diabetes and chronickidney disease (CKD) in diastolic heart failure is highbut not particularly higher than in systolic heart diseaseIn general both diastolic and systolic heart failure exhibitdistinctive subjective symptoms and objective findings ofheart failure including dyspnea edema and malaise Symp-toms of diastolic heart failure typically include dyspnea dueto pulmonary congestion particularly shortness of breathparoxysmal atrial fibrillation and rapidly developing dyspneainduced by tachycardia all of which are common initialsymptoms By contrast in systolic heart failure symptomsand signs due to general malaise and organ hypoperfusionassociated with decreased cardiac output are frequently seen

The main differences between diastolic and systolic heartfailure are the presence of contractile dysfunction and leftventricular remodeling (Table 1) In systolic heart failureprogressive ventricular dilatation or eccentric cardiac hyper-trophy can be seen By contrast diastolic heart failureexhibits concentric ventricular remodelingwithout dilatationor concentric cardiac hypertrophy The tissue Doppler EE1015840ratio (early mitral inflow peak velocityearly diastolic mitralannular velocity) is an established diastolic function indexthat is not affected by hemodynamic load but increases in


Table 1 Comparison of systolic and diastolic heart failure

Systolic heart failure Diastolic heart failure

LV remodelingEccentric hypertrophy Concentric remodeling

Concentric hypertrophy

LV end-diastolic volume uarr rarr

LV end-diastolic pressure uarr uarr

LV ejection fraction darr rarr

LV dPdt darr rarr

LV stiffness rarr uarr

1198641198641015840

uarr uarr

LA dilatation + +BNP or NT-proBNP uarr uarr

LV left ventricular 1198641198641015840 early mitral flow velocityearly diastolic mitral annular velocity ratio LA left arterial BNP brain natriuretic peptide

both diastolic and systolic heart failure Pattern of pulmonaryvein flow and EA (ratio of early to late mitral inflow peakvelocity) are also established as major diastolic functionalindices though they are rather dependent on hemodynamicstatus [14]

In recent years several reports on important associa-tion of various biomarkers for heart failure and subtypesof heart failure have been published [15ndash19] Accordingto those reports plasma B-type natriuretic peptide (BNP)concentration in patients with HFpEF is lower than that inpatients with HFrEF [15] Nonetheless at a given level ofBNP the prognosis in patients with HFpEF is as poor asin those with HFrEF [15] Not only BNP and N-terminalproBNP (NT-proBNP) but also high sensitive troponin T(hsTnT) was significantly associated with the risk for HFrEF[16] On the other hand growth differentiation factor 15(GDF15) cystatin C and urinary albumin excretion weresignificantly associated with the risk for HFpEF [16 17]Researchers suggest that biomarkers relevant to myocardialinjury (TnT) and myocardial stress (BNP NT-proBNP andmidregional proadrenomedullin) have significant relationwith HFrEF [17ndash19] and biomarkers relevant to extracellularmatrix remodeling (Galectin-3 and GDF15) have significantrelation with HFpEF [17ndash19]

6 The Pathogenesis of Diastolic Heart Failure

The histological features of systolic heart failure includemyocardial hypertrophy loss ofmyocardial cells and restruc-turing of the extracellular matrix Meanwhile significantmyocardial fibrosis together with myocardial hypertrophyis typical in diastolic heart failure Myocardial fibrosis isthought to be the main factor in increased stiffness [14]

Mechanical stimulation to the myocardium is the mainfactor of myocardial hypertrophy while myocardial fibrosismay be caused by humoral factors such as various cytokinesgrowth factors and hormones In hypertensiveHFpEFmodelrats oxidative stress was increased and angiotensin II was

produced within the arterial walls due to high blood pres-sure This resulted in fibroblast activation and increasedproduction of transforming growth factor-120573 via macrophageinfiltration and activation mediated by monocyte chemo-tactic protein-1 The resulting perivascular inflammation isreported to be the cause of reactive fibrosis of myocardium[14ndash16] InDahl salt-sensitive ratHFpEFmodels it was foundthat endothelin together with angiotensin II is an importantmediator of myocardial fibrosis [17]

In addition to the quantitative increase in collagenand distribution abnormalities qualitative changes are alsoinvolved in increased myocardial stiffness caused by fibrosisIn Dahl salt-sensitive rat HFpEF models the increase in theratio of stiff type I collagen to type III collagenwhich is highlydistensible and increased collagen cross-linking are reportedto important factors of increased myocardial stiffness [18]

In diastolic heart failure myocardial stiffness of car-diomyocytes per se also increases Detailed mechanism forthis remains unclear but is thought to be due to changes instructural proteins associated with myocardial hypertrophyTitin which is a giant sarcomeric protein acts as a molec-ular spring and plays a large part in the distensibility ofcardiomyocytes during diastole However in diastolic heartfailure compared with systolic heart failure the ratio of largedistensible N2A isoforms small rigid N2B isoforms to wasfound to decrease [19]

7 Therapeutic Options

To date angiotensin converting enzyme inhibitors (ACEIs)angiotensin receptor blockers (ARB) beta-blockers andstatins have been tried for HFpEF Although they areauthorized for optimal treatment for HFrEF none of themcan provide the optimal treatment for HFpEF [2] ACEIperindopril was tested for HFpEF patients for the first timein PEPndashCHF trial [20] It showed no difference in mortal-ity andor hospitalization rate for heart failure CHARM-preserved trial in which ARB candesartan was tested for


cardiovascular mortality and heart failure hospitalizationsfailed to demonstrate a beneficial effect on cardiovasculardeath but observed fewer heart failure hospitalizations inthe candesartan group [21] I-PRESERVE was so far thelargest trial for HFpEF using ARB irbesartan or placeboMortality or hospitalization rate for cardiovascular causeswas again not improved by irbesartan [22] In OPTIMIZE-HF registry discharge use of beta-blockers exerted no effecton one-year mortality or hospitalization rate in HFpEFpatients [23] A preliminary report suggested statin ther-apy to be beneficial in HFpEF with lower mortality rate[24]

A neutral outcome in HFpEF compared with a positiveoutcome in HFrEF as occurred with ACEIs ARBs and beta-blockers might be compatible with flawed study designHowever a positive outcome in HFpEF compared with aneutral outcome in HFrEF as occurred with statins canno longer be attributable to study design but supportsdifferent signal transductions drivingmyocardial remodelingin HFpEF and HFrEF [25]

Several compounds seem to be promising for drugtarget of HFpEF Phosphodiesterase 5 inhibitors (PDE5I)increase cGMP level attenuate adrenergic stimulationreduce ventricular-arterial stiffening antagonizemaladaptivechamber remodeling improve endothelial function andreduce pulmonary vascular resistance [26ndash30] The PDE5Isildenafil is currently being tested in the RELAX trial whichevaluates the effects of PDE5I on exercise capacity functionalstatus and ventricular function [31] A preliminary open-label trial documented improvements in exercise capacityand the EE1015840 ratio in HFpEF treated with spironolactone[32] Aldosterone antagonists are currently being activelyinvestigated for HFpEF in the clinical situation Chamberstiffness is altered by the extracellular matrix like colla-gen Alagebrium chloride (ALT-711) is a novel agent thatbreaks glucose cross-links and improves ventricular andvascular compliance in animal experiments and reducesblood pressure and vascular stiffness in humans [33 34]Small open-label trial revealed that ALT-711 was associatedwith reduced LV mass and improved diastolic filling [35]Diastolic dysfunction in HFpEF may be related to abnor-malities in energy availability or utilization in myocytes[36ndash38] Recently abnormal ATP phosphocreatine shuttlekinetics in HFpEF was demonstrated and similar resultswere recently also reported [37 39] Currently a noveltherapy targeting energy utilization is under investigation[40]

8 Conclusion

Despite the fact that diastolic heart failure is a commoncondition of heart failure its precise definition still remainsunclear Therefore the similarities and differences betweenthe pathogenesis and pathophysiology of diastolic and sys-tolic heart failure have not been sufficiently elucidatedThis is thought to be the most significant reason for alack of established treatment methods for diastolic heartfailure We hope to proceed with future studies on thispaper

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this article

References

[1] M Ouzounian D S Lee and P P Liu ldquoDiastolic heartfailure mechanisms and controversiesrdquoNature Clinical PracticeCardiovascular Medicine vol 5 pp 375ndash386 2008

[2] M T Maeder and D M Kaye ldquoHeart failure with normal leftventricular ejection fractionrdquo Journal of the American College ofCardiology vol 53 no 11 pp 905ndash918 2009

[3] B A Borlaug and W J Paulus ldquoHeart failure with preservedejection fraction pathophysiology diagnosis and treatmentrdquoEuropean Heart Journal vol 32 no 6 pp 670ndash679 2011

[4] E H Garcıa E R Perna E F Farıas et al ldquoReduced systolicperformance by tissue Doppler in patients with preservedand abnormal ejection fraction new insights in chronic heartfailurerdquo International Journal of Cardiology vol 108 no 2 pp181ndash188 2006

[5] G Yip M Wang Y Zhang J W H Fung P Y Ho and JE Sanderson ldquoLeft ventricular long axis function in diastolicheart failure is reduced in both diastole and systole time for aredefinitionrdquo Heart vol 87 no 2 pp 121ndash125 2002

[6] S J Skaluba and S E Litwin ldquoMechanisms of exercise intol-erance insights from tissue Doppler imagingrdquo Circulation vol109 no 8 pp 972ndash977 2004

[7] K Yamamoto Y Sakata T Ohtani Y Takeda and T ManoldquoHeart failure with preserved ejection fraction what is knownand unknownrdquo Circulation Journal vol 73 no 3 pp 404ndash4102009

[8] S A Hunt W T Abraham M H Chin et al ldquoACCAHA2005 guideline update for the diagnosis and management ofchronic heart failure in the adult a report of the AmericanCollege of CardiologyAmerican Heart Association Task Forceon Practice Guidelines (Writing Committee to Update the2001 Guidelines for the Evaluation and Management of HeartFailure) developed in collaboration with the American Collegeof Chest Physicians and the International Society for Heart andLung Transplantation endorsed by the Heart Rhythm SocietyrdquoCirculation vol 112 no 12 pp e154ndashe235 2005

[9] R S Vasan and D Levy ldquoDefining diastolic heart failure a callfor standardized diagnostic criteriardquo Circulation vol 101 no 17pp 2118ndash2121 2000

[10] M R Zile W H Gaasch J D Carroll et al ldquoHeart failure witha normal ejection fraction is measurement of diastolic functionnecessary to make the diagnosis of diastolic heart failurerdquoCirculation vol 104 no 7 pp 779ndash782 2001

[11] M R Zile C F Baicu and W H Gaasch ldquoDiastolic heartfailuremdashabnormalities in active relaxation and passive stiffnessof the left ventriclerdquoThe New England Journal of Medicine vol350 no 19 pp 1953ndash1959 2004

[12] T E Owan D O Hodge R M Herges S J Jacobsen V LRoger and M M Redfield ldquoTrends in prevalence and outcomeof heart failure with preserved ejection fractionrdquo The NewEngland Journal of Medicine vol 355 no 3 pp 251ndash259 2006

[13] R S Bhatia J V Tu D S Lee et al ldquoOutcome of heart failurewith preserved ejection fraction in a population-based studyrdquoThe New England Journal of Medicine vol 355 no 3 pp 260ndash269 2006


[14] S F Nagueh C P Appleton T C Gillebert et al ldquoRecommen-dations for the evaluation of left ventricular diastolic functionby echocardiographyrdquo European Journal of Echocardiographyvol 10 no 2 pp 165ndash193 2009

[15] D J van Veldhuisen G C Linssen T Jaarsma et al ldquoB-type natriuretic Peptide and prognosis in heart failure patientswith preserved and reduced ejection fractionrdquo Journal of theAmerican College of Cardiology vol 61 no 14 pp 1498ndash15062013

[16] F P Brouwers R A de Boer P van der Harst et al ldquoIncidenceand epidemiology of new onset heart failure with preserved vsreduced ejection fraction in a community-based cohort 11-yearfollow-up of PREVENDrdquo European Heart Journal vol 34 pp1424ndash1431 2013

[17] R Santhanakrishnan J P Chong T P Ng et al ldquoGrowthdifferentiation factor 15 ST2 high-sensitivity troponin T andN-terminal pro brain natriuretic peptide in heart failure withpreserved vs reduced ejection fractionrdquo European Journal ofHeart Failure vol 14 pp 1338ndash1347 2012

[18] R R J van Kimmenade and J L Januzzi Jr ldquoEmerging bio-markers in heart failurerdquo Clinical Chemistry vol 58 no 1 pp127ndash138 2012

[19] H K Gaggin and J L Januzzi Jr ldquoBiomarkers and diagnosticsin heart failurerdquo Biochimica et Biophysica Acta 2013

[20] J G F Cleland M Tendera J Adamus N Freemantle LPolonski and J Taylor ldquoThe perindopril in elderly peoplewith chronic heart failure (PEP-CHF) studyrdquo European HeartJournal vol 27 no 19 pp 2338ndash2345 2006

[21] S YusufMA Pfeffer K Swedberg et al ldquoEffects of candesartanin patients with chronic heart failure and preserved left-ventricular ejection fraction the CHARM-preserved trialrdquoTheLancet vol 362 no 9386 pp 777ndash781 2003

[22] B M Massie P E Carson J J McMurray et al ldquoIrbesartanin patients with heart failure and preserved ejection fractionrdquoTheNew England Journal of Medicine vol 359 no 23 pp 2456ndash2467 2008

[23] A F Hernandez B G Hammill C M OrsquoConnor K A Schul-man L H Curtis and G C Fonarow ldquoClinical effectiveness ofbeta-blockers in heart failure Findings from the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment inHospitalized Patients With Heart Failure) Registryrdquo Journal ofthe American College of Cardiology vol 53 no 2 pp 184ndash1922009

[24] H FukutaD C Sane S Brucks andWC Little ldquoStatin therapymay be associatedwith lowermortality in patients with diastolicheart failure a preliminary reportrdquo Circulation vol 112 no 3pp 357ndash363 2005

[25] W J Paulus and J JM van Ballegoij ldquoTreatment of heart failurewith normal ejection fraction an inconvenient truthrdquo Journalof the American College of Cardiology vol 55 no 6 pp 526ndash5372010

[26] B A Borlaug V Melenovsky T Marhin P Fitzgerald andD A Kass ldquoSildenafil inhibits 120573-adrenergic-stimulated cardiaccontractility in humansrdquo Circulation vol 112 no 17 pp 2642ndash2649 2005

[27] C Vlachopoulos K Hirata and M F OrsquoRourke ldquoEffect ofsildenafil on arterial stiffness and wave reflectionrdquo VascularMedicine vol 8 no 4 pp 243ndash248 2003

[28] S D Katz K Balidemaj S Homma H Wu J Wang andS Maybaum ldquoAcute type 5 phosphodiesterase inhibition withsildenafil enhances flow-mediated vasodilation in patients with

chronic heart failurerdquo Journal of the American College ofCardiology vol 36 no 3 pp 845ndash851 2000

[29] G D Lewis J Lachmann J Camuso et al ldquoSildenafil improvesexercise hemodynamics and oxygen uptake in patients withsystolic heart failurerdquoCirculation vol 115 no 1 pp 59ndash66 2007

[30] H H Chen ldquoHeart failure a state of brain natriuretic peptidedeficiency or resistance or bothrdquo Journal of the AmericanCollege of Cardiology vol 49 no 10 pp 1089ndash1091 2007

[31] M M Redfield K L Lee and E Braunwald ldquoEvaluatingthe effectiveness of Sildenafil at improving health outcomesand exercise ability in people with diastolic heart failure (TheRELAX Study)rdquo NCT00763867 2008 httpclinicaltrialsgov

[32] K R Daniel G Wells K Stewart B Moore and D W Kitz-man ldquoEffect of aldosterone antagonism on exercise tolerancedoppler diastolic function and quality of life in older womenwith diastolic heart failurerdquoCongestive Heart Failure vol 15 no2 pp 68ndash74 2009

[33] P V Vaitkevicius M Lane H Spurgeon et al ldquoA cross-link breaker has sustained effects on arterial and ventricularproperties in older rhesusmonkeysrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 98 no3 pp 1171ndash1175 2001

[34] D A Kass E P Shapiro M Kawaguchi et al ldquoImprovedarterial compliance by a novel advanced glycation end-productcrosslink breakerrdquo Circulation vol 104 no 13 pp 1464ndash14702001

[35] W C Little M R Zile D W Kitzman W G Hundley T XOrsquoBrien and R C Degroof ldquoThe effect of alagebrium chloride(ALT-711) a novel glucose cross-link breaker in the treatmentof elderly patientswith diastolic heart failurerdquo Journal of CardiacFailure vol 11 no 3 pp 191ndash195 2005

[36] B A Borlaug V Melenovsky S D Russell et al ldquoImpairedchronotropic and vasodilator reserves limit exercise capacity inpatients with heart failure and a preserved ejection fractionrdquoCirculation vol 114 no 20 pp 2138ndash2147 2006

[37] T T Phan K Abozguia G Nallur Shivu et al ldquoHeart failurewith preserved ejection fraction is characterized by dynamicimpairment of active relaxation and contraction of the leftventricle on exercise and associated with myocardial energydeficiencyrdquo Journal of the American College of Cardiology vol54 no 5 pp 402ndash409 2009

[38] D W Kitzman M B Higginbotham F R Cobb K H Sheikhand M J Sullivan ldquoExercise intolerance in patients with heartfailure and preserved left ventricular systolic function failure ofthe Frank-Starling mechanismrdquo Journal of the American Collegeof Cardiology vol 17 no 5 pp 1065ndash1072 1991

[39] C S Smith P A Bottomley S P Schulman G Gerstenblithand R G Weiss ldquoAltered creatine kinase adenosine triphos-phate kinetics in failing hypertrophied human myocardiumrdquoCirculation vol 114 no 11 pp 1151ndash1158 2006

[40] M Frenneaux ldquoPerhexiline therapy in heart failure withpreserved ejection fraction syndromerdquo NCT00839228 2009httpclinicaltrialsgov

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


End-systolicpressure-volume

LV p

ress

ure

LV volume

Diastolic failure

End-diastolicpressure-volume

relationship

Normal

relationship = Emax

(a)

LV p

ress

ure

LV volume

Elevation of LV

End-diastolic pressure

(b)

Figure 1 (a) The end-systolic pressure-volume relationship is the same as a normal heart in diastolic heart failure but the end-diastolicpressure-volume relationship shifts upwards As a result left ventricular end-diastolic pressure rises (b) In pathologies with diastolicdysfunction when an abrupt increase in blood pressure occurs the pressure-volume loop shifts to the upper right without decrease in 119864maxTherefore pulmonary congestion is induced as a result of the significant increase in left ventricular end-diastolic pressure LV left ventricular

pressure rises In pathologies with diastolic dysfunctionwhen an abrupt increase in blood pressure occurs thepressure-volume loop shifts to the upper right withoutdecrease in 119864max (absolute index of contractibility) There-fore pulmonary congestion is induced as a result of thesignificant increase in left ventricular end-diastolic pressure(Figure 1(b))

By contrast in systolic dysfunction left ventricular con-tractile function decreases and 119864max gets smaller (Figure 2)Meanwhile the end-diastolic pressure-volume relationshipshifts downwards rather than remaining unchanged Tomaintain cardiac output the pressure-volume loop shiftsright due to increase in preloadTherefore the left ventricularpressure-volume loop operates on the steep part of the end-diastolic pressure-volume curve consequently causing end-diastolic pressure to rise

3 Are Diastolic Dysfunction and SystolicDysfunction Separate Diseases

In diastolic dysfunction contractility of whole left ventricleis considered normal However the contractile velocity insystole measured with tissue Doppler decreased in both sys-tolic and diastolic dysfunction [4] Furthermore local con-tractility in longitudinal direction is known to be impairedlocally in diastolic heart failure [5] Recent findings suggestthat contractility decreases even in diastolic heart failurein myocardium level By contrast diastolic function is alsoimpaired in systolic heart failure and has been shown todecrease exercise tolerance and be one of the determinantsof prognosis [6]Therefore diastolic and systolic heart failure

are not considered to be independent and separate entitiesThe single syndrome hypothesis of heart failure is thereforeadvocated (Figure 3) [1] In that hypothesis heart failure is asingle continuous disease spectrum and systolic and diastolicheart failure are phenotypes at two extremes

Thus there is the ldquogrey zonerdquo in diagnosing HFrEF withLVEF of 45 to 50 or 45 to 55 In other words some ofHFpEFwith LVEF of 45 to 55might be diagnosed as HFrEFrather than HFpEF As shown in Figure 3 a phenotype ofheart failure comprised of some extent of systolic dysfunctionand some extent of diastolic function Heart failure withLVEF of 45 to 55 would be located in the middle of thecontinuum of disease spectrum

By contrast some researchers have advocated that dias-tolic function is not something that should only be notedin the pathogenesis of diastolic heart failure but shouldbe widely viewed as a determinant of pathophysiology inheart failure [7] Heart dysfunction that occurs as a result ofheart disease causes diastolic dysfunction Among such casesthere exist patients with concurrent systolic dysfunctionFurthermore a portion of patients with heart dysfunctionclinically exhibit symptoms of heart failure Among themthose with significant systolic dysfunction where the mainpathology is systolic heart failure and diastolic dysfunctionare said to have diastolic heart failure

4 The Diagnostic Criteria for DiastolicHeart Failure

Definition of systolic heart failure is reduction of the leftventricular ejection fraction Thus its diagnosis is quite easyBy contrast diagnosis of diastolic heart failure is difficult


Decrease


LV p

ress

ure

LV volume

in Emax
























LV dPdt darr rarr


1198641198641015840

uarr uarr

















8 Conclusion




References
















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Decrease


LV p

ress

ure

LV volume

in Emax
























LV dPdt darr rarr


1198641198641015840

uarr uarr

















8 Conclusion




References
















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























LV dPdt darr rarr


1198641198641015840

uarr uarr

















8 Conclusion




References
















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















8 Conclusion




References
















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article similarities and differences between the … · 2019. 7. 31. · to diastolic heart...

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