Intraventricular Pressure Gradients in Heart Failure

PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (p in ) • ISSN 1802-9973 (online) © 2013 Ins i u e o Physiology . .i., Academy o Sciences o he Czech Republic, P ague, Czech Republic Fax +420 241 062 164, e-mail: phys [email protected], www.biomed.cas.cz/physiol es Physiol. Res. 62: 479-487, 2013 In a en icula P essu e G adien s in Hea Failu e M. GUERRA1, C. BRÁS-SILVA1, M. J. AMORIM1, C. MOURA1, P. BASTOS1, A. F. LEITE-MOREIRA1 1Depa men o Physiology and Ca dio ho acic Su ge y, Ca dio ascula R&D Uni , Facul y o Medicine, Uni e si y o Po o, Po o, Po ugal Recei ed Feb ua y 18, 2013 Accep ed July 4, 2013 On-line Sep embe 10, 2013 Summa y The aim o he p esen s udy was o cha ac e ize in a en icula p essu e g adien s (IVPGs) in an animal model o ch onic hea ailu e. New Zealand abbi s we e ea ed wi h doxo ubicin (hea ailu e g oup, n=5) o saline (con ol g oup, n=5) and ins umen ed wi h p essu e ca he e s placed in he apex and ou low- ac o le en icle (LV) and wi h sonomic ome e c ys als placed in he apex and base o he LV ee wall. In hea ailu e animals, en icula illing was delayed and slowe when compa ed wi h con ol animals. Mo eo e , he physiological nonuni o mi y obse ed be ween apical and basal segmen s in no mal hea s was abolished in ailing hea s. Simul aneously, physiological IVPGs obse ed du ing no mal en icula illing we e en i ely los in hea ailu e animals. Du ing en icula emp ying physiological nonuni o mi y be ween apical and basal segmen s obse ed in con ol animals was also abolished in hea ailu e animals. In ailing hea s minimal leng h occu ed la e and almos a same ime bo h in apical and in basal myoca dial segmen s. Simul aneously, he cha ac e is ic IVPG pa e n obse ed in heal hy hea s du ing sys ole, which p omo es en icula emp ying, was no obse ed in ailing hea s. The p esen s udy showed ha dias olic IVPGs, a ma ke o no mal en icula illing, and sys olic IVPGs, a ma ke o no mal en icula emp ying, a e abolished in hea ailu e. Key wo ds In a en icula • G adien s • Hea ailu e • Dias ole • Sys ole • Myoca dial segmen s Co esponding au ho A. F. Lei e-Mo ei a, Depa men o Physiology and Ca dio ho acic Su ge y, Ca dio ascula R&D Uni , Facul y o Medicine, Uni e si y o Po o, Alameda P o esso He nâni Mon ei o, 4200-319 Po o, Po ugal. Fax: 00351225513646. E-mail: [email p o ec ed] In oduc ion Cou ois e al. (1988) desc ibed o he i s ime, in a canine model, in a en icula p essu e g adien s (IVPGs) du ing dias ole and la e showed ha hese dias olic g adien s we e diminished by ischemia and ela ed o sys olic unc ion (Cou ois e al. 1990). Recen ly, we ex ended hose obse a ions also in an animal model. We con i med no only he exis ence o dias olic bu also sys olic IVPGs in he le en icle (LV) and demons a ed, o he i s ime, ha hey a e modula ed by physiological nonuni o mi y (B u sae e al. 1987) be ween basal and apical myoca dial segmen s (Gue a e al. 2013). Mo eo e , we showed ha dias olic and sys olic IVPGs, a ma ke o no mal segmen al unc ion, can be a enua ed, los en i ely o e en e e sed when en icula emp ying is opposed by a e load ele a ions o a e egional acu e ischemia (Gue a e al. 2013). Fu he mo e, Fi s enbe g e al. (2008) showed ha imp o emen s in LV sys olic and dias olic unc ion, h ough su gical myoca dial e ascula iza ion in pa ien s wi h ischemic ca diomyopa hy, co ela e di ec ly wi h he eco e y o dias olic IVPGs. Ro ne e al. (2005) also demons a ed ha dias olic IVPGs augmen a ion and LV elaxa ion imp o emen wi h exe cise a e signi ican ly impai ed in hea ailu e pa ien s. Howe e , sys olic and dias olic IVPGs we e ne e ca e ully obse ed and cha ac e ized, namely hei magni ude and hei beha io in he p esence o sys olic and/o dias olic dys unc ion, in ch onic models o hea ailu e (S ugaa d e al. 1993, S eine e al. 2002). In ac , he p ac ical alue o IVPGs in 480 Gue a e al. Vol. 62 unde s anding en icula pa hophysiology is enhanced by he ecogni ion o i s gene al applicabili y and quan i ica ion no only in acu e models, bu also in ch onic models (De Boeck e al. 2005, Yo i e al. 2005a,b). Dias olic and sys olic IVPGs may e lec in insic p ope ies and ch onic dys unc ion o he LV and no only an acu e ans al ula low diso de (Fi s enbe g e al. 2001, Gue a e al. 2011b). In his se ing, he p esen s udy was conduc ed o cha ac e ize dias olic and sys olic IVPGs in an animal model o ch onic hea ailu e, and co ela e IVPGs wi h dias olic and sys olic segmen al LV dys unc ion and nonuni o mi y. Me hods The in es iga ion con o ms o he Guide o he Ca e and Use o Labo a o y Animals published by he US Na ional Ins i u es o Heal h (NIH publica ion no. 85-23, Re ised 1996), and all animals ecei ed human ca e in compliance wi h he Eu opean Con en ion on Animal Ca e. S udy was also app o ed by he E hics Commi ee o ou Uni e si y. Ch onic hea ailu e model A well-documen ed egimen was used o he induc ion o hea ailu e due o doxo ubicin oxici y (A nolda e al. 1985, B ás-Sil a e al. 2008). Adul male New Zealand Whi e abbi s (O yc olagus cuniculus, 3.0±0.2 kg) ecei ed doxo ubicin ia a ma ginal ea ein by bolus injec ion (1 mg/kg) wice weekly o 8 weeks (n=5) ollowed by a washou pe iod o 1 week. Con ol abbi s (n=5) ecei ed he ehicle (0.9 % saline) in equi olume ic doses o e he same pe iod. All animals we e e alua ed by echoca diog aphy a he beginning and e e y wo weeks du ing he adminis a ion o doxo ubicin o ehicle. Echoca diog aphic examina ion was pe o med as p e iously desc ibed (Fon es-Sousa e al. 2009). B ie ly, he abbi s we e ligh ly anes he ized wi h an in amuscula combina ion o ke amine hyd ochlo ide (2 mg/kg) and mede omidine hyd ochlo ide (0.15 mg/kg), being allowed o b ea h spon aneously. The animals we e placed p one on a able wi h an a ea emo ed so ha he ul asound p obe could be b ough om below and placed on a sha ed a ea o he an e io ches wall. The echoca diog ams we e ob ained using a 7.5 MHz ansduce (Vi id 3 Gene al Elec ics echoca diog aph, Po ugal) and he examina ion was pe o med om he igh pa as e nal sho -axis iew. Two-dimensional guided M-mode acings we e made jus below he mi al al e a he le el o he papilla y muscles o measu emen s o he le en icula in e nal diame e and he le en icula wall was ee in dias ole and sys ole. Th ee ep esen a i e cycles we e measu ed and a e aged o each abbi a each ime poin . Analyzed pa ame e s we e: hea a e, an e io and pos e io end-dias olic and end-sys olic wall hickness, le en icula end-sys olic and end-dias olic diame e s, and ac ional sho ening. Expe imen al p epa a ion Animal p epa a ion The ins umen a ion o he animals o hemodynamic s udies was pe o med one week a e he las adminis a ion o he ehicle (n=5) o doxo ubicin (n=5), espec i ely, as p e iously desc ibed (Lei e- Mo ei a and Co eia-Pin o 2001). In summa y, animals we e p emedica ed wi h ke amine hyd ochlo ide (50 mg kg−1, I.M., Ke ala ®, P ize Limi ed) and xylazine hyd ochlo ide (5 mg kg−1, I.M., Rompum®, Baye ). A emo al ein was cannula ed, and a in a enous solu ion con aining 20 meq KCl and 40 meq NaHCO3 in 500 ml o 0.9 % NaCl was adminis a ed a a a e o 8 ml kg−1 h−1 o compensa e o pe iope a i e luid losses. A acheos omy was pe o med, and mechanical en ila ion was ini ia ed (Ha a d Small Animal Ven ila o , model 683), deli e ing oxygen-en iched ai . Respi a o y a e and idal olume we e adjus ed o keep a e ial blood gases and pH wi hin physiological limi s. Gene al anes hesia was main ained by in a enous in usion o midazolam (0.07 mg kg−1 h−1, Midazolam B. B aun), en anil (0.003 mg kg−1 h −1, Fen anil B. B aun) and ecu onium (0.1 mg kg−1 h−1, No cu on®, O ganon) o achie e adequa e dep h o anes hesia o absence o a co neal e lex. A 20 gauge ca he e was inse ed in he igh emo al a e y and connec ed o a p essu e ansduce o moni o hea a e and a e ial p essu e and o ob ain samples o blood gas analysis. The hea was exposed by a median s e no omy, and he pe ica dium was opened wide. A limb lead elec oca diog am be ween he le leg elec ode and he igh a m elec ode (DII) was eco ded h oughou . T ansien ao ic cons ic ions we e pe o med by ab up ly occluding he ao a wi h a silk su u e placed a ound he ascending ao a du ing he dias ole sepa a ing wo hea bea s. This was achie ed by pushing a plas ic ube agains he ao a wi h one hand while pulling he silk su u e wi h he o he hand. Ao ic cons ic ion was quickly eleased o a oid neu ohumo al e lex changes in ca diac unc ion (Co eia-Pin o e al. 2013 IVPGs in Hea Failu e 481 2006). Peak sys olic p essu e o iso olume ic hea bea s, which can be ob ained wi h ao ic occlusions, is a sensi i e index o le en icula con ac ili y. P essu e measu emen s Two 3 F ench high- ideli y mic omanome e s (SPR-524; Milla Ins umen s, Hous on, TX, USA) we e inse ed h ough an apical punc u e wound in o he LV ca i y. One was pulled ca e ully back owa ds he endoca dium and secu ed in place wi h a pu se-s ing su u e o measu e apical le en icula p essu e (LVP). The o he was in oduced un il we could see he impac om he ao ic al e on he p essu e ace. The ca he e hen was pulled back 3 mm below he ao ic al e so ha i was loca ed in he LV ou low ac o measu e basal LVP. The p essu e ansduce s we e calib a ed agains a me cu y column and ze oed a e s abiliza ion o 30 min in a wa e ba h a body empe a u e. The ze o was se a he le el o he igh a ium. Reco dings we e made wi h espi a ion suspended a end expi a ion. Pa ame e s we e con e ed online o digi al da a wi h a sampling equency o 1 kHz. Le en icula p essu es we e measu ed a end dias ole (LVPED), a p essu e nadi (LVPmin) and a peak sys ole (LVPmax). Peak a es o LV p essu e ise (dP/d max) and p essu e all (dP/d min), as well as ime o dP/d min, we e also measu ed. Relaxa ion a e was es ima ed wi h he ime cons an τ by i ing he iso olume ic p essu e all o a monoexponen ial unc ion. We eco ded he IVPG con inuously as apical minus ou low- ac LVP. Peak and a e age (a ea di ided by du a ion) IVPGs we e calcula ed du ing dias olic and sys olic phases o he ca diac cycle. Sonomic ome y Regional en icula unc ion was measu ed wi h wo pai s o ul asonic segmen leng h gauges implan ed in he ci cum e en ial di ec ion o apical and basal le en icula an e io midwall and connec ed o a sonomic ome e ampli ie sys em (T i on Technology, San Diego, CA, USA). A he end o he expe imen , he animal was eu hanized by adminis a ion o an o e dose o anes he ic agen s, and he posi ions o he c ys als and mic omanome e s we e e i ied a pos mo em examina ion. Segmen leng hs we e measu ed a he end dias ole (ED leng h), a dP/d max and a mi al al e opening (MVO). Minimal segmen leng h (Leng hmin) was measu ed as he minimal leng h p eceding o coinciding wi h peak –dP/d min. F ac ional sho ening was calcula ed as he pe cen age segmen leng h change om end dias ole o dP/d min. Expe imen al p o ocol A e comple e ins umen a ion, we allowed he animal p epa a ion o s abilize o 30 min be o e he beginning o he expe imen al p o ocol, which consis ed in measu ing apex o ou low- ac p essu e g adien s and apical and basal myoca dial segmen leng hs in con ol and hea ailu e animals du ing baseline and a e loaded hea bea s. The animals we e no paced, bu hea a e did no a y signi ican ly du ing he expe imen al p o ocol. S a is ical analysis S a is ical analysis was pe o med using SPSS 17.0 so wa e. G oup da a a e p esen ed as means ± SEM and we e compa ed using wo-way ANOVA. S uden -Newman-Keuls es was selec ed o pe o m pai wise mul iple compa isons when signi ican di e ences we e de ec ed. S a is ical signi icance was assumed a a wo ailed alue o P<0.05. Resul s Ca diac hemodynamics and echoca diog aphy The hemodynamic ea u es o he expe imen al g oups a e summa ized in Table 1. In compa ison wi h he con ol g oup, he hea ailu e g oup p esen ed a lowe sys olic p essu e, dP/d max, peak sys olic iso olume ic p essu e and ac ional sho enning. The le en icula illing p essu e, as es ima ed by le en icula end-dias olic p essu e, was inc eased in ailing hea s, whe eas he dP/d min was dec eased and he elaxa ion ime cons an τ was inc eased. Fu he mo e, he echoca diog aphic e alua ion in he hea ailu e g oup demons a ed a p og essi e inc ease o he end-dias olic ( om 14.2±0.3 o 15.2±0.3 mm) and end-sys olic ( om 9.9±0.2 o 11.1±0.3 mm) sho -axis diame e s and a educ ion in ac ional sho ening ( om 32±1 o 26±1 %) and ejec ion ac ion ( om 64±1 o 56±2 %) o he le en icle. This was consis en wi h he p esence o dila ed ca diomyopa hy and hea ailu e. Mo eo e , in he p esen s udy he animals had clea signs o hea ailu e such as u led hai , labo ed en ila ion, asci es and pleu al e usion. 482 Gue a e al. Vol. 62 Table 1. Sys olic and dias olic pa ame e s in con ol and hea ailu e animals. Con ol Hea ailu e Apex Ou low ac Apex Ou low ac LVPED (mm Hg) 3.3±0.2 3.2±0.3 3.9±0.2α 4.0±0.2α dP/d max (mm Hg/s) 3791±667 3669±627 1187±182α 1103±155α LVPmax (mm Hg) 80.7±4.6 80.8±4.7 49.1±5.5α 48.6±5.1α dP/d min (mm Hg/s) -3598±664 -4631±564β -1070±241α -1098±234α LVPISO (mm Hg/s) 148.9±9.2 149.7±9.8 84.6±13.5α 82.6±11.3α Time o dP/d min (ms) 140±2 129±1β 191±11α 190±9α LVPmin (mm Hg) 2.7±0.6 2.0±1.6 2.9±0.4 3.3±0.5 Time o LVPmin (ms) 214±8 231±4β 268±9α 272±7α τ (ms) 15.0±1.3 10.6±0.6β 30.4±1.9α 28.4±2.2α ED leng h (mm) 6.90±0.33 7.35±0.89 7.33±0.54 7.82±1.22 Leng h a dP/d max (mm) 6.97±0.27 7.39±0.67 7.44±0.76 7.98±0.79 Leng hmin (mm) 5.89±0.34 6.28±0.78 6.92±1,38 6.72±1,64 Time o leng hmin (ms) 213±10 170±16β 268±86α 291±56α Leng h a dP/d min (mm) 6.20±0.32 6.32±0.42 6.99±1.22 7.12±0.96 Leng h a MVO (mm) 6.00±0.20 6.22±0.23 6.78±0.98 6.98±1.43 F ac ional sho enning (%) 12.7±1.9 14.3±1.1 6.2±2.9α 7.9±1.3α Hea a e (bpm) 170±11 181±7 α P<0.05 e sus no mal; β P<0.05 e sus apex. Abb e ia ions: LVPED, end dias olic le en icula p essu e; dP/d max, peak a e o le en icula p essu e ise; LVPmax, peak sys olic le en icula p essu e; dP/d min, peak a e o le en icula p essu e all; LVPISO, peak sys olic p essu e in a iso olume ic bea ; LVPmin, le en icula p essu e nadi ; τ, ime cons an o iso olume ic elaxa ion a e; ED leng h, end dias olic segmen leng h; Leng hmin, minimal segmen leng h; MVO, mi al al e opening. Table 2. Apex- o-ou low ac mean p essu e g adien s (in mm Hg) h oughou he ca diac cycle a baseline and du ing a e load ele a ion in con ol and hea ailu e animals. Dias ole Sys ole Ea ly dias ole Ven icula illing A ial con ac ion Rapid ejec ion Slow ejec ion Con ol Baseline -5.1±0.7 +3.4±0.2 +0.6±0.1 +0.5±0.1 -0.9±0.1 A e load -1.5±0.3α +3.7±0.2 +0.5±0.1 -0.8±0.1α -0.9±0.1 Hea ailu e Baseline -0.5±0.1β +0.1±0.1β +0.4±0.1 +1.0±0.2 +0.7±0.2β A e load -0.5±0.2β +0.1±0.2β +0.4±0.2 +2.3±0.3α,β +1.8±0.3α,β α P<0.05 e sus baseline; β P<0.05 e sus con ol. IVPGs changes in hea ailu e Figu e 1 ep esen s le en icula apical and ou low ac p essu es, as well as, simul aneous eco ding o he apex- o-ou low ac IVPG along ca diac cycle in wo ep esen a i e examples, one o a no mal and one o a hea ailu e animal. Table 2 summa izes mean IVPGs h oughou he ca diac cycle in con ol and hea ailu e animals du ing baseline and a e loaded ca diac bea s. In heal hy hea s o con ol animals, du ing he apid phase o en icula illing, we eco ded a –5.1±0.5 mm Hg IVPG om he ou low- ac o he 2013 IVPGs in Hea Failu e 483 apex. La e , when apical p essu e s a ed o ise, he ou low- ac p essu e con inued o all, hus c ea ing a +3.6±0.2 mm Hg apex o ou low- ac p essu e g adien . Du ing sys ole we eco ded a biphasic IVPG pa e n, mani es ed as a posi i e g adien (+0.6±0.1 mm Hg) om apex o ou low- ac du ing apid ejec ion, which was ollowed by a nega i e g adien om he ou low- ac o he apex du ing he slow ejec ion phase (–0.8±0.1 mm Hg). Fig. 1. Le en icula apical (–––) and ou low ac (----) p essu es and simul aneous eco ding o apex- o-ou low ac IVPG (g ay) along ca diac cycle in a ep esen a i e no mal s hea ailu e animal. No mal: Du ing dias ole we obse ed a signi ican ou low ac - o-apex IVPG in he ea ly dias ole (a) and an apex- o-ou low ac IVPG in he la e dias ole (b); du ing ea ly sys ole we eco ded an IVPG om apex- o-ou low (c) which in e s du ing la e sys ole (d). Hea Failu e: Dias olic IVPGs obse ed du ing no mal en icula illing we e en i ely los in ailing hea s, while du ing sys ole we obse ed only one apex- o-ou low- ac g adien h oughou en icula emp ying ( c ’). In ailing en icles o hea ailu e animals, dias olic en icula illing was delayed and slowe , as indica ed by he inc ease in imes o apical and basal peak dP/d min and o LVP nadi . Mo eo e , he nonuni o mi y (measu ed as dis inc imings a which minimum leng h was achie ed be ween di e en en icula segmen s du ing ca diac cycle) obse ed be ween apical and basal segmen s in heal hy hea s was abolished in hea ailu e. In ac , as e ou low- ac elaxa ion (assessed by dP/d min and by he ime cons an τ) obse ed in heal hy hea s was no obse ed in ailing hea s whe e elaxa ion occu ed a he same momen in he apex and in he ou low- ac (Table 1, Time o LVPmin). Simul aneously, dias olic IVPGs we e en i ely los in hea ailu e animals, and no di e ences we e eco ded be ween ou low- ac and apical LV p essu es du ing en icula illing (Fig. 1, Hea Failu e). Du ing en icula emp ying as e con ac ion o basal in compa ison o apical myoca dial segmen s eco ded in heal hy hea s (assessed by a sho e ime o minimal leng h o a simila myoca dial sho ening) was also abolished in hea ailu e animals. In ailing hea s minimal leng h occu ed la e and almos a same ime bo h in apical and in basal myoca dial segmen s (Table 1, Time o lengh min). Simul aneously, he physiological biphasic IVPG pa e n obse ed in heal hy hea s du ing sys ole was no obse ed in ailing hea s (Fig. 1, Hea Failu e). Addi ionally, he esponse o a e load ele a ion was also 484 Gue a e al. Vol. 62 dis inc in he ailing hea s, which may ep esen a sensi i e indica o o LV con ac ili y impai men (Table 2). Discussion The p esen s udy showed ha dias olic IVPGs, a ma ke o no mal en icula illing, and sys olic IVPGs, a ma ke o no mal en icula emp ying, a e abolished in ailing hea s. P e iously, we demons a ed ha dias olic and sys olic IVPGs a e modula ed by physiological nonuni o mi y be ween basal and apical myoca dial segmen s and ha IVPGs can be a enua ed, los en i ely o e en e e sed when en icula emp ying is opposed by a e load ele a ions o a e egional acu e ischemia (Gue a e al. 2013). So, we hypo hesized ha any condi ion ha in e e es wi h he no mal segmen al unc ion, such as ch onic hea ailu e, migh be expec ed o al e he physiological IVPGs h oughou he ca diac cycle. In ac , dila ed en icles a e poo suc ion pumps, aspi a ing a ela i ely small olume in ea ly illing and compensa ing wi h a ial con ac ion and a es ing achyca dia o main ain ca diac ou pu (Li le 2005). Heal hy en icles s o e g ea e amoun s o elas ic ene gy du ing sys ole and a e he e o e mo e e ec i e suc ion pumps du ing dias ole (Gilbe and Glan z 1989). In his con ex , educed dias olic IVPGs a e he consequence no only o a lowe impulse due o dep essed elas ic ecoil, bu also o ela i ely highe dele e ious con ec i e o ces and impai ed en icula elaxa ion, which ad e sely a ec LV illing (Nikolic e al. 1995). In ou animal model, he p og ession o ca diac dys unc ion was moni o ed echoca diog aphically o es ima e mo phologic and unc ional al e a ions du ing he de elopmen o hea ailu e. Hemodynamic s udies pe o med wo weeks a e he las adminis a ion o doxo ubicin and he las echoca diog aphic e alua ion clea ly showed he p esence o sys olic and dias olic dys unc ion in hea ailu e animals. In compa ison wi h he con ol g oup, he hea ailu e g oup p esen ed signi ican ly lowe sys olic p essu es, dP/d max, peak sys olic iso olume ic p essu es and ac ional sho ening, consis en wi h he p esence o dila ed ca diomyopa hy and hea ailu e. In ac , doxo ubicin is an an h acycline widely used in cy os a ic ea men s which causes a dose-dependen ca dio oxici y and hus has been used o induce hea ailu e in a ious animal species (Gomes e al. 2012). Doxo ubicin-induced ca diomyopa hy is cha ac e ized by en icula wall hinning and dila a ion, and dep essed sys olic and dias olic unc ion accompanied by luid e en ion and by neu ohumo al ac i a ion (Chekano 1999). A he ca diac muscle le el, i p omo es in insic con ac ile dys unc ion and educed con ac ile ese e. Fu he mo e, doxo ubicin impai s ascula as well as endoca dial endo helial unc ion and induces in lamma o y eac ions in he hea , leading o h ombosis in he a ia and myoca di is (Gaudin e al. 1993). Mul iple pa hways o an h acycline-induced ca diac cellula inju y ha e been p oposed such as he elease o ca dio oxic subs ances, which subsequen ly accumula e in he ca diomyocy es, he gene a ion o ee adical, lipid pe oxida ion, and supp ession o DNA, RNA and p o ein syn hesis (Sawye e al. 2010, Adão e al. 2013). In he p esen s udy he animals had clea signs o hea ailu e, which we e mo e compa ible wi h he in asi e hemodynamic measu emen s han wi h he mo e modes echoca diog aphic dep ession. As echoca diog aphic eco dings we e pe o med e e y wo weeks, he las echoca diog aphic e alua ion was ca ied ou wo weeks be o e he hemodynamic measu emen s. Gi en he apid p og ession o he disease a e six weeks, his migh explain he di e en pheno ypes a he wo dis inc ime poin s. Mo eo e , echoca diog aphy is no a sensi i e me hod o de ec ing signi ican di e ences o wall hickening in hese small hea s. In hea ailu e animals, he no mal base- o-apex IVPG obse ed du ing ea ly dias ole was en i ely abolished, showing impai men o en icula illing. La e dias olic apex- o-base IVPG was also los in ailing hea s which may comp omise he beginning o nex en icula emp ying. In ac , dias olic IVPGs migh be causally ela ed o ecoil o en icula walls in conjunc ion wi h elease o elas ic ene gy s o ed du ing he p e ious sys ole, which gene a es suc ion and con ibu es o no mal illing (Cou ois e al. 1990). In ca diomyopa hic hea s, abno mal dias olic mo emen o dyskine ic segmen s du ing iso olume ic elaxa ion could impa some mo ion o blood pooled in he apical and an e io egions o he en icle and hus con ibu e o he al e a ion o he no mal dias olic IVPGs (Beppu e al. 1988, Delema e e al. 1988). Mo eo e , some elas ic po en ial ene gy s o ed du ing sys ole could be p ema u ely los du ing ea ly dias ole in ailing hea s which may impai en icula illing and abolish no mal ea ly and la e dias olic IVPGs (Smise h e al. 1998). Thus, acu e o ch onic en icula dys unc ion, by 2013 IVPGs in Hea Failu e 485 diminishing he amoun o unc ional en icula myoca dium a ailable o con ac ion and subsequen elas ic ecoil in one egion o he en icle, should esul in loss o diminu ion o he dias olic IVPG in ha egion (Gue a e al. 2013). Du ing sys ole, he no mal IVPG pa e n obse ed in heal hy hea s, and cha ac e ized by an apex o ou low- ac g adien du ing apid ejec ion ollowed by an ou low- ac o apex g adien du ing he slow ejec ion phase, was also los in ailing hea s. In no mal hea s, sys olic IVPG pa e n pa allels he physiological ao ic- en icula p essu e g adien s obse ed be ween ao a and he LV wi h ao ic p essu e being lowe han LV p essu e du ing apid ejec ion and highe du ing he slow ejec ion phase. In hea ailu e animals, physiological biphasic IVPGs du ing sys ole we e no obse ed, which may impai no mal en icula emp ying. As a po en ial limi a ion, we mus acknowledge ha he p esen s udy was pe o med in anes he ized open-ches and open-pe ica dium animals wi h wo p essu e ca he e s ied a he le el o he LV apex and wo myoca dial segmen leng h gauges placed in he apex and base o he LV ee wall. These manipula ions may impai en icula con ac ili y, as well as, may al e longi udinal unc ion and o sion he eby a ec ing apex o base g adien s. We mus howe e unde sco e ha he ca he e s and segmen leng h gauges a e a he lexible and small, minimizing he nega i e impac on LV unc ion. Mo eo e , as bo h g oups (hea ailu e and con ol) we e submi ed o he same su gical manipula ion such impac should ha e been simila , he e o e making i accep able o compa e IVPGs in he wo g oups (Gue a e al. 2011a). In conclusion, egional al e a ions in IVPGs migh be an impo an ac o in he cha ac e is ic changes ha occu in in a en icula low in speci ic ca diac diso de s. IVPGs play a physiological ole in he heal hy hea ha is los in pa hological condi ions, which may con ibu e o and ep esen an ea ly sign o en icula dys unc ion. In his way IVPGs eco ding and s udy may gi e impo an no el insigh in o he comp ehension o hea ailu e pa hophysiology. Mo eo e , ou indings migh be ele an o be e unde s and he pa hophysiology o doxo ubicin-induced ca diomyopa hy so ha we can de elop e icien p o ec i e and/o he apeu ic s a egies in pa ien s ea ed wi h his chemo he apeu ic agen . Con lic o In e es The e is no con lic o in e es . Acknowledgemen s This wo k was suppo ed by a g an om he Po uguese Founda ion o Science and Technology (FCT: PEs -C/SAU/UI0051/2011; EXCL/BIM-MEC/055/2012 h ough Ca dio ascula R&D Uni ) and om he Eu opean Commission (FP7-Heal h-2010; MEDIA- 261409). C. 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