Unlocking the Mysteries of Diastolic Function Deciphering the Rosetta Stone 10 Years Later

It has now been a quarter of a century since the first description by Kitabatake and his associates of the use of echo-Doppler to characterize the transmitral flow velocity curves in various disease states. A decade ago we described the role of echocardiography in the “Evaluation of Diastolic Filling of Left Ventricle in Health and Disease: Doppler Echocardiography Is the Clinician’s Rosetta Stone.” Over the ensuing decade, advances in echo-Doppler have helped to further decipher the morphologic and physiological expression of cardiovascular disease and unlock additional mysteries of diastology. The purpose of this review is to highlight the developments in echo-Doppler and refinements in our knowledge that have occurred over the past decade that enhance our understanding of diastology

Flow propagation velocity is not a simple index of diastolic function in early filling. A comparative study of early diastolic strain rate and strain rate propagation, flow and flow propagation in normal and reduced diastolic function

BACKGROUND: Strain Rate Imaging shows the filling phases of the left ventricle to consist of a wave of myocardial stretching, propagating from base to apex. The propagation velocity of the strain rate wave is reduced in delayed relaxation. This study examined the relation between the propagation velocity of strain rate in the myocardium and the propagation velocity of flow during early filling. METHODS: 12 normal subjects and 13 patients with treated hypertension and normal systolic function were studied. Patients and controls differed significantly in diastolic early mitral flow measurements, peak early diastolic tissue velocity and peak early diastolic strain rate, showing delayed relaxation in the patient group. There were no significant differences in EF or diastolic diameter. RESULTS: Strain rate propagation velocity was reduced in the patient group while flow propagation velocity was increased. There was a negative correlation (R = -0.57) between strain rate propagation and deceleration time of the mitral flow E-wave (R = -0.51) and between strain rate propagation and flow propagation velocity and there was a positive correlation (R = 0.67) between the ratio between peak mitral flow velocity / strain rate propagation velocity and flow propagation velocity. CONCLUSION: The present study shows strain rate propagation to be a measure of filling time, but flow propagation to be a function of both flow velocity and strain rate propagation. Thus flow propagation is not a simple index of diastolic function in delayed relaxation

What parameters affect left ventricular diastolic flow propagation velocity? in vitro studies using color m-mode doppler echocardiography

BACKGROUND: Insufficient data describe the relationship of hemodynamic parameters to left ventricular (LV) diastolic flow propagation velocity (Vp) measured using color M-mode Doppler echocardiography. METHODS: An in vitro LV model used to simulate LV diastolic inflow with Vp measured under conditions of varying: 1) Stroke volume, 2) heart rate (HR), 3) LV volume, 4) LV compliance, and 5) transmitral flow (TMF) waveforms (Type 1: constant low diastasis flow and Type 2: no diastasis flow). RESULTS: Univariate analysis revealed excellent correlations of Vp with stroke volume (r = 0.98), LV compliance (r = 0.94), and HR with Type 1 TMF (r = 0.97). However, with Type 2 TMF, HR was not associated with Vp. LV volume was not related to Vp under low compliance, but inversely related to Vp under high compliance conditions (r = -0.56). CONCLUSION: These in vitro findings may help elucidate the relationship of hemodynamic parameters to early diastolic LV filling

Increased LV apical untwist during preload reduction in healthy humans. An echocardiographic speckle tracking study during lower body negative pressure (LBNP)

Background: We sought to investigate the effect of reduced preload on LV untwist and early diastolic filling in healthy individuals. Methods: Twelve healthy men, 22 (22,23) years of age, were examined at rest and during applied lower body negative pressure (LBNP) of -20 mmHg and -40 mmHg, respectively. Regional untwist and untwist rate during IVRT were calculated at LV basal, papillary, sub-papillary and apical short axis levels by two dimensional speckle tracking echocardiography. LV early diastolic filling was assessed by transmitral E-wave (E) peak velocity by pulsed Doppler and flow propagation velocity (Vp) by color M-mode Doppler and early diastolic pulsed Doppler tissue velocities (E`) from septal and lateral mitral annulus. Results: From rest to LBNP -40 mmHg the LV untwist and untwist rate at sub-papillary level increased from 2.3 (1.4,3.5) to 4.5 (3.1,7.6) degrees and from -36 (-51,-25) to -69 (-127,-42) °/s (p<0.001, p=0.003), respectively, while apical untwist and untwist rate increased from 3.9 (2.3,4.3) to 7.6 (6.4,10.5) degrees and from -51 (-69,-40) to -118 (-170,-84) °/s (p<0.001, p<0.001), respectively. Since untwist and untwist rate at the basal level were unchanged, this created markedly larger base to apical untwist and untwist rate gradients from rest to LBNP -40 mmHg. E, Vp and E` were reduced by 34, 32 and 39 %, respectively. Conclusions: LV untwist and untwist rate during IVRT were increased at apical levels, which might be a physiological mechanism to minimize the impairment in LV early diastolic filling during preload reduction

RT-PCR basert mutasjonsanalyse av BRCA1/2 i eggstokkreft

Bryst- og eggstokkreft er to av de vanligste krefttypene og rammer i hovedsak kvinner. Breast cancer gene 1/2 (BRCA 1/2) er to gener der mutasjoner, både arvelige og somatiske, kan forårsake disse krefttypene. Avhengig av mutasjonsstatus i disse genene, så kan det åpne for å gi vedlikeholdsbehandling med en poly (ADP-Ribose) polymerase 1 (PARP1)-inhibitor. Dette er en farmakologisk inhibitor, som hemmer PARP enzymer. Disse enzymene har kritiske funksjoner innen reparasjon av DNA-skader. Tumorceller med en mutert BRCA1/2 variant er vesentlig mer sensitiv for PARP1-inhibitorer enn normale celler, da de ofte mangler disse reparasjonsmekanismene. PARP1-inhibitorer kan derfor benyttes som behandlingsform til bryst- og eggstokkreft. Dagens metode for å teste mutasjoner i BRCA1/2 er basert på Ion Torrent neste generasjons sekvensering (NGS). Denne metoden kan gi usikre resultater i enkelte tilfeller, da fragmentering av nukleinsyrer er et problem i formalinfikserte, parafininnstøpte (FFPE) vevsprøver. Dette kan gjøre enkelte typer mutasjoner, som store eksondelesjoner, vanskelig å påvise. På bakgrunn av dette var det ønskelig å finne en metode for å kunne verifisere usikre resultater fra NGS-analyser, og det ved å benytte RT-PCR og sangersekvensering på isolert RNA fra FFPE vevsprøver. RNA ble isolert fra tumorrike områder i tre FFPE vevsprøver med påviste eksondelesjoner, og fra tre normale prøver som kontroll. Som kvalitetskontroll ble RNA-konsentrasjonen målt og kvaliteten til prøvene ble sjekket ved real-time RT-PCR med β-actin som kontroll. Av prøvene ble cDNA-syntese og PCR med spesifikke primere gjort, før gelelektroforese ble benyttet for å kontrollere størrelsen på PCR-produkter. Til slutt ble relevante PCR-produkter sekvensert og analysert med kapillærelektroforese for å bekrefte mutasjonene. Resultatene etter sekvensering og dataanalyse, viste at eksondelesjonene ble påvist og bekreftet med denne metoden, men resultatet var avhengige av kvaliteten på det opprinnelige prøvematerialet. Av prøvene med eksondelesjoner, så var prøve 2 av for lav kvalitet og ga ikke et tilfredsstillende resultat. Både prøve 1 og 3, samt de normale prøvene som ble benyttet som kontroller, ga forventede resultater, selv med relativt lav prøvekvalitet. Resultatene viste at denne metoden er egnet til å påvise store eksondelesjoner i BRCA1/2 fra FFPE vevsprøver, ved bruk av RT-PCR og sangersekvensering. Den kan derfor benyttes som et alternativ til å verifisere Ion Torrent NGS-analyser, hvis disse gir usikre resultater. Det må dog tas forbehold om at metoden bare er testet på et lite antall prøver. Metoden må testes i større grad for å kunne trekke en definitiv konklusjon