Gunnar Plehn

Left Ventricular Diastolic Dysfunction as an Early Manifestation of Diabetic Cardiomyopathy

Aims/Hypothesis: Early determination of myocardial manifestations of diabetes mellitus is of major importance, since myocardial involvement considerably influences the prognosis of diabetic patients. The aim of this study was to investigate whether young patients with insulin-dependent diabetes mellitus and normal systolic left ventricular (LV) function already show a diastolic LV dysfunction and an increased risk of arrhythmias. Methods: Echocardiography was performed in 87 patients suffering from type I diabetes mellitus, without known cardiac disease and in 87 controls. Patients with a known manifest cardiac disease or a long-term diabetic syndrome were excluded. Morphological parameters were determined using M-mode echocardiography. Doppler echocardiography was used to evaluate parameters of LV diastolic function. The risk of arrhythmia was assessed by means of electrocardiography, heart rate variability, and late potential analysis. Results: The left atrial and ventricular dimensions and systolic functional parameters of all patients were normal. A diastolic dysfunction with a reduction in early diastolic filling, an increase in atrial filling, an extension of isovolumetric relaxation and deceleration time was documented in diabetic patients, as well as an increased number of supraventricular and ventricular premature beats. Conclusion: Even young patients with diabetes mellitus suffer from a diastolic dysfunction while systolic ventricular function is normal. Therefore, echocardiography with measurements of diastolic functional parameters appears to be a sensitive method for evaluating the manifestation and course of early diabetic cardiomyopathy.

Left Ventricular Hypertrophy and Diastolic Dysfunction in Healthy Pregnant Women

Objective: The purpose of this study was to examine which hemodynamic parameters change under the natural volume overload of pregnancy. Study Design: 46 healthy pregnant women were echocardiographically examined during the course of pregnancy. To evaluate left ventricular diastolic function, mitral inflow and pulmonary venous flow profiles were used. Fractional shortening and left ventricular muscle mass were calculated. Results: In the course of pregnancy the left ventricular muscle mass index increased (from 66 ± 6 to 96 ± 9 g/m2), fractional shortening decreased (from 38 ± 4 to 32 ± 6%) and a disturbed diastolic relaxation pattern was documented. Eight weeks after delivery, all left ventricular systolic and diastolic functional parameters returned to normal values. Conclusion: The natural volume overload in pregnancy leads to a reversible ‘physiological’ left ventricular hypertrophy, a short-term decrease in systolic function and a significant change in left ventricular diastolic function.

Left ventricular diastolic function in physiologic and pathologic hypertrophy

BACKGROUND Patients with hypertensive heart disease and left ventricular hypertrophy demonstrate an impaired left ventricular diastolic filling pattern. The aim of this study was to find out whether physiologic left ventricular hypertrophy induced by endurance training causes disturbances in left ventricular systolic and diastolic filling. METHODS We examined 49 athletes with left ventricular (LV) hypertrophy due to endurance training, 49 patients with LV hypertrophy due to arterial hypertension, and 26 untrained healthy control subjects by conventional echocardiography. Parameters of LV diastolic filling using pulse wave and color flow Doppler were also assessed. RESULTS All three study groups showed normal fractional shortening and mid-wall fractional shortening. Conventional echocardiography revealed a higher LV muscle mass index in the two study groups compared with the controls (athletes, 99 +/- 10 g; hypertensive patients, 95 +/- 11 g: controls: 52 +/- 7 g; P < .01 for athletes and hypertensive patients). In patients with arterial hypertension, a diastolic dysfunction consisting of a delayed relaxation pattern with a decrease in maximal early velocity of diastolic filling (0.44 +/- 0.1 m/sec) and a compensatory increase of the maximal late velocity of diastolic filling (0.53 +/- 0.1 m/sec) was demonstrated. In athletes with physiologic LV hypertrophy, a normal LV diastolic filling pattern was documented. CONCLUSIONS Doppler echocardiographic parameters of LV diastolic function can be of diagnostic importance for discrimination between pathologic and physiologic LV hypertrophy.

Relevance of hemostatic risk factors on coronary morphology in patients with diabetes mellitus type 2.

ObjectiveThe influence hemostatitc parameters on the morphological extent and severity of coronary artery disease were studied in patients with and without DM type 2.BackgroundIt is known that patients with diabetes (DM) have abnormal metabolic and hemostatic parametersMethodsOf 150 consecutive patients with angiographically proven coronary artery disease 29 presented with DM. Additionally to parameters of lipid-metabolism fibrinogen, tissue-plasminogenactivator (t-PA), plasminogen-activator-inhibitor (PAI), plasmin-a-antiplasmin (PAP), prothrombin-fragment 1+2 (F1+2), thrombin-antithrombin (TAT), von-willebrand-factor (vWF), platelet factor 4 (PF4), glykomembranproteine 140 (GMP140) and the rheologic parameters plasma viscosity and red blood cell aggregation were evaluated. The extent and severity of CAD was evaluated according to the criteria of the American Heart Association.ResultsPatients with DM presented with a higher number of conventional risk factors as compared to non-diabetic patients. Additionally there were significant differences for F1+2, red blood cell aggregation and PAI. Diabetic patients showed a more severe extent of coronary arteriosclerosis, which also could be found more distally. A significant relationship between blood-glucose, thrombocyte-activation (vWF), endogenous fibrinolysis (PAI) and the severity of CAD and a more distal location of stenoses could be found (r = 0.6, p < 0.001).ConclusionPatients with coronary artery disease and DM type 2 showed marked alterations of metabolic, hemostatic, fibrinolytic and rheologic parameters, which can produce a prothrombogenic state. A direct association of thrombogenic factors on coronary morphology could be shown. This can be the pathophysiologic mechanism of more severe and distal pronounced coronary atherosclerosis in these patients.

Pulmonary Vein Isolation in 2012: Is It Necessary to Perform a Time Consuming Electrophysical Mapping or Should We Focus on Rapid and Safe Therapies? A Retrospective Analysis of Different Ablation Tools

Background: Pulmonary Vein Isolation (PVI) is evolving as an established treatment option in atrial fibrillation (AF). Different fluoroscopy-guided ablation devices exist either on the basis of expandable circumferential and mesh designs with mapping and ablation of pulmonary vein potentials, or of a balloon technology, a “single shot” device with a purely anatomical approach. Systematic comparisons between procedure duration (PD), fluoroscopy time (FT) and clinical outcome in using different ablation tools are lacking in the literature. Methods: In a single center retrospective analysis, 119 PVI procedures were performed between August 2008 and March 2011 in paroxysmal AF (PAF, 59.7%) and persistent AF (persAF, 40.3%) patients with mean age of 59.4±10.3 years and history of AF since 8.1±9.7 months. The PVI procedures were evaluated by comparing PD and FT using I) the High Density Mesh Mapper (HDMM), II) the High Density Mesh Ablator (HDMA), and III) the Arctic Front® Cryoballoon. The primary endpoints were FT and PD, the secondary endpoint was procedural safety and efficacy in short- and longterm follow-up. Results: The procedures performed for 119 patients (63.0 % male) included 42 PVIs with the HDMM (35.3 %), 47 with the HDMA (39.5 %) and 30 with the cryoballoon (25.2 %). Comparing the 30 first procedures in groups of 10 in the HDMM and HDMA group, PD and FT fell in the HDMM group (PD from 257.5 to 220.9 min and FT from 80.5 to 67.3 min, both p < 0.05) as well as in the HDMA group (PD from 182.9 to 147.2 min and FT from 41.02 to 29.1 min, both p < 0.05). In the cryoballoon group, there was a steep learning curve with a steady state after the first 10 procedures (PD and FT decreased significantly from 189.5 to 138.1 min and 36.9 to 27.3 min, p values 0.005 and 0.05 respectively). With respect to recurrence of AF in a 24 months follow up, the HDMM and cryoballoon group showed comparable results with ~72% of patients free of arrhythmias. None of the patients died due to severe complications, or suffered a hemodynamic relevant pericardial effusion and/or stroke. Impairment of the phrenic nerve was observed in three patients. Conclusion: Use of the cryoballoon technology was associated with a steep learning curve and a reduced PD and FT; the long-term outcome was similar compared with the HDMM group. The efficacy and safety of the devices but also PD and FT should be respected as the strongest indicators of the quality of ablation. Further studies with long time follow-ups will show if the time for correct mapping of the PV potentials is a price we should be willing to pay or if we should adopt a “wait-and-see” attitude referring the AF recurrence.

ARTERIA THORACICA INTERNA-BYPASS : GRUNDLAGEN DER DOPPLERSONOGRAPHIE FUR DIE PRA- UND POSTOPERATIVE DIAGNOSTIK

Die Verwendung der Arteria thoracica interna zur koronaren Revaskularisierung hat sich in den letzten 25 Jahren als Gefäß der Wahl etabliert. Neben dem etablierten Verfahren der Angiographie wird in den letzten Jahren die Duplexsonographie zunehmend als nicht invasives bildgebendes Verfahren zur Untersuchung dieses Gefäßes eingesetzt. Bei der präoperativen Evaluierung von 117 Patienten konnte im Vergleich zur Angiographie bei einem hohen Anteil der Patienten ein übereinstimmendes Untersuchungsergebnis festgestellt werden. Während in der präoperativen Phase das Strompulskurvenprofil entsprechend der arteriellen Versorgung eines Skelettmuskels durch einen hohen systolischen Anteil dominiert wird, kommt es zu einer postoperativen Anpassung an das koronararterielle Strombett in Form eines vermehrten diastolischen Flußanteils. Diese nicht invasiven Befunde der transthorakalen Duplexsonographie konnten durch invasive intravaskuläre Dopplermessungen bestätigt werden. Ebenso wie beim präoperativen Vergleich ergibt sich auch postoperativ ein hohes Maß an Übereinstimmung zwischen Angiographie und Duplexsonographie bei der Beurteilung des Revaskularisationsergebnisses. Im Hinblick auf die zunehmende Verwendung der Arteria thoracica interna als Bypassgefäß sollte dieses nicht invasive Verfahren zunehmend an Bedeutung gewinnen. During the last 25 years the internal thoracic artery has become a well established conduit for coronary revascularization. Next to angiography, duplex-sonography is increasingly used as a non-invasive imaging procedure for the evaluation of this graft vessel. Preoperative investigation in 117 patients has yielded a high level of agreement between angiography and duplex-sonography. While the preoperative flow-pattern is dominated by systolic flow as it is typical for vessels supplying skeletal muscule, the postoperative findings show an adaptation to the coronary vascular bed as the diastolic flow increases. These non-invasive measurements are well matched with invasive intravascular recordings. Coronary angiography and duplex-sonography of the internal thoracic artery yielded comparable findings in respect to the procedural result. Considering the increasing use of the internal thoracic artery in coronary artery bypass surgery, this non-invasive method should gain increasing relevance.

Prognostische Relevanz linksventrikulärer diastolischer Funktionsparameter bei dilatativer Kardiomyopathie

Patients with dilated cardiomyopathy (DCM) generally have an impaired functional capacity and poor long-term outcomes. A mortality of 5–15% per year has been described actually. Aim of this study was to verify the prognostic relevance of invasive and non-invasive parameters of diastolic function in patients with DCM.    In 33 patients with DCM, cardiac catheterization was performed and left ventricular systolic (ejection fraction (EF; %)); left ventricular enddiastolic pressure (LVEDP; mmHg) and diastolic function (time constant of relaxation (T, ms); the constant of myocardial stiffness (b) were derived from biplane laevocardiography and simultaneous micromanometric registration of pressure-volume curves. For evaluation of clinical out-come, the follow-up period was defined as beginning on the day after cardiac catheterization and ending on the most recent date or with a cardiac event (death or cardiac transplantation). All patients were reevaluated for NYHA functional class and completed a standard questionnaire. The following hemodynamic parameters were evaluated: invasive parameters of left ventricular diastolic function (constant of relaxation: tau (ms), constant of myocardial stiffness: b)), as well as parameters of systolic function (ejection fraction (EF; %)), left ventricular pressure (LVEDP; mmHg), left ventricular muscle mass index (LVMMI; g/m2), left ventricular enddiastolic volume index (LVEDVI; ml/m2) and non-invasive parameters of morphological data, left ventricular systolic (fractional shortening (FS, %) and ejection fraction) and diastolic parameters with echocardiography.    During the follow-up period of 36 months, 11 of 33 patients experienced a major cardiac event (cardiac death n=8, heart transplantion n=3). The major cause of death was progressive pump failure. The remaining 22 patients were further classified with respect to changes in functional status. While clinical symptoms could be improved medically in patients with moderate increase of myocardial stiffness, patients with severe increase of myocardial stiffness (b: 76.1±12.1 vs 17.9±+8.1, p<0.001) could not be improved and suffered more cardiac events. Doppler echocardiographic measurements in these patients showed a restrictive filling pattern (VE 0.91±0.21 vs 0.64±0.18 m/s; p<0.01; VA 0.52±0.23 vs 0.57±0.24 m/s; p<0.01, deceleration time 129±17 vs 211±14 ms; p<0.01). The medical heart failure therapy was comparable in both groups.    In patients with cardiac events, the diastolic left ventricular variables did not significantly differ between patients who underwent heart transplantation and those who died. Patients who demonstrated a sole impairment of relaxation (tau: >50 ms) suffered no cardiac events.    Impaired diastolic function contributes to the clinical picture of congestive heart failure. Parameters of left ventricular diastolic function are powerful and important predictors of major cardiac events in patients with DCM, like heart transplantion and non-sudden death, and may indicate future clinical success of medical treatment. Invasive and non-invasive parameters of diastolic function reveal comparable information for the estimation of prognosis of patients with DCM in order to initiate early therapy. Die dilatative Kardiomyopathie (DCM) fasst Erkrankungen des Herzmuskels mit Verminderung der kontraktilen Funktion und Vergrößerung der Herzhöhlen zusammen. In neueren Studien wurde über eine Mortalität von 5–15% pro Jahr berichtet. Ziel unserer Untersuchung war die Analyse invasiver und nicht-invasiver diastolischer Funktionsparameter zur Beurteilung der Prognose bei Patienten mit DCM.    Insgesamt wurde bei 33 Patienten mit DCM die linksventrikuläre Funktion mittels biplaner LV-Angiographie und simultaner Mikromanometrie erfasst. Vor der Herzkatheteruntersuchung erfolgten eine Einteilung der Patienten nach der NYHA-Klassifikation und eine echokardiographische Ausgangsuntersuchung. Es wurden invasiv gemessene Parameter der diastolischen Funktion (Zeitkonstante der Relaxation: Tau (ms), Steifigkeitsindex: b), sowie der systolischen Funktion (Auswurffraktion (EF; %)), linksventrikulärer Druck (LVEDP; mmHg), linksventrikulärer Muskelmassenindex (LVMMI; g/m2), linksventrikulärer enddiastolischer Volumenindex (LVEDVI; ml/m2) erfasst. Mittels Echokardiographie erfolgte die Bestimmung morphologischer Parameter, systolischer (Fraktionale Verkürzungsfraktion; Ejektionsfraktion) und diastolischer Funktionsparameter.    Während der Nachbeobachtungszeit von 36 Monaten starben 8 Patienten an progredienter Herzinsuffizienz, bei 3 Patienten musste eine Herztransplantation vorgenommen werden. Bei diesen 11 Patienten zeigte sich im Vergleich mit den übrigen 22 Patienten in der invasiven Diagnostik ein signifikant (p<0,001) erhöhter Steifigkeitsindex (b: 76,1±12,1 vs 17,9±8,1), eine pathologisch verlängerte Zeitkonstante Tau des isovolumetrischen Druckabfalls (Tau: 59,2±17,3 ms; Normwert 40–45 ms) und dopplerechokardiographisch ein „restriktives” Füllungsmuster mit einem steilen frühdiastolischen Maximum (VE 0,91±0,21 vs 0,64±0,18 m/s; p<0,01) und kleinerem atrialen Füllungsanteil (VA 0,52±0,23 vs 0,57+0,24 m/s; p<0,01). Die Dezelerationszeit des frühdiastolischen Geschwindigkeitsmaximums war deutlich kürzer als bei den Überlebenden (129±17 vs 211±14 ms; p<0,01). Die medikamentöse Herzinsuffizienztherapie unterschied sich in beiden Patientenkollektiven nicht. Bei Patienten mit alleiniger Relaxationsstörung zeigte sich ein benigner Verlauf.    Fazit: Sowohl die Zeitkonstante der Relaxation als auch der Steifigkeitsindex sind prognostische Prädiktoren einer erhöhten Sterblichkeit bei Patienten mit DCM. Die Doppler-echokardiographische Analyse des diastolischen Einstromprofils liefert vergleichbare Informationen zur Prognoseabschätzung im Krankheitsverlauf von Patienten mit DCM. Beide Methoden erlauben zum Zeitpunkt der Diagnose die Prognose abzuschätzen und eine entsprechende Therapie frühzeitig einzuleiten.

Alterations of left ventricular function in women with insulin-dependent diabetes mellitus during pregnancy.

Aims/hypothesisDuring pregnancy, eminent cardiovascular changes occur. The aim of the following study was to investigate the course of haemodynamic parameters under the increased volume load during pregnancy and delivery in women with insulin-dependent diabetes mellitus.MethodsWe examined 51 pregnant diabetic women and 51 healthy pregnant women. The control group consisted of 51 healthy non-pregnant women. In all women, left ventricular mass and fractional shortening were calculated. To evaluate left ventricular diastolic function, mitral inflow and pulmonary venous flow profiles were analysed.ResultsDuring pregnancy left ventricular mass increased, fractional shortening decreased and diastolic dysfunction was found. While the healthy pregnant women developed signs of disturbed relaxation during pregnancy, pregnant diabetic women showed signs of a disturbed relaxation at the beginning of gestation. Of the pregnant diabetic women, 29 developed a restrictive filling pattern at the 24th week of gestation. The remaining 22 diabetic women had a comparable restrictive filling pattern only during vaginal delivery. In 10 of the 29 pregnant diabetic women dangerous complications were documented, while there were no complications in the healthy pregnant women and the other 22 diabetic pregnant women.Conclusion/interpretationIn healthy women pregnancy results in a reversible physiologic left ventricular hypertrophy, a disturbed relaxation pattern and a temporary decrease of left ventricular systolic function. In contrast, pregnant diabetic women showed a delayed relaxation at the beginning of pregnancy and developed a restrictive filling pattern. The early development of a restrictive filling pattern could indicate complications during delivery in pregnant diabetic women.

Linksventrikuläre diastolische Funktion in der Schwangerschaft bei Patientinnen mit arterieller Hypertonie Eine prospektive Untersuchung mittels M-mode-Echokardiographie und Doppler-Echokardiographie

Introduction During pregnancy eminent cardiovascular changes occur. The aim of the following study was to investigate the course of hemodynamic parameters under increased volume load during pregnancy in women suffering from mild arterial hypertension. Methods Altogether 47 women (age: 25±4 years) with mild arterial hypertension detected during pregnancy underwent echocardiography at the 9th, 24th and 33rd week of gestation. Furthermore echocardiography was performed postpartum at weeks 1 and 8. The control group comprised 45 healthy pregnant women. In all patients left ventricular muscle mass index and systolic shortening fraction were measured. The following Doppler echocardiographic parameters were ascertained: peak early diastolic and peak late diastolic flow, VE/VA ratio, acceleration time, deceleration time and isovolumetric relaxation time. Results During pregnancy all patients had an increase of left ventricular muscle mass index and a decrease of fractional shortening. All patients developed a relevant diastolic dysfunction. While the control group developed signs of disturbed relaxation as reduction of peak early diastolic flow (0.89± 0.07 versus 0.82±0.08 m/s*), VE/VA ratio and an increase of isovolumetric relaxation time (72±12 versus 123±7*) at the 33rd week of gestation (* p<0.01), all pregnant women with mild arterial hypertension developed a diastolic dysfunction with signs of delayed relaxation already at the beginning of gestation. 26 pregnant women with arterial hypertension developed a restrictive diastolic filling pattern at 24 weeks of gestation. The other 21 pregnant women only showed restriction for a short time at the end of gestation.    In healthy pregnant women, volume load results in a reversible physiologic left ventricular hypertrophia, a significant alteration of diastolic left ventricular function in terms of a disturbed relaxation pattern and a temporary decrease of systolic function. In comparison hypertensive pregnant women show a delayed relaxation at the beginning of pregnancy and 50% developed early signs of restrictive cardiomyopathy. These changes may predispose to critical complications during pregnancy. Einleitung Am Herz-Kreislaufsystem vollziehen sich während der Schwangerschaft erhebliche Veränderungen. Ziel der Studie war es zu untersuchen, in welcher Weise sich hämodynamische Parameter unter der „physiologischen” Volumenbelastung der Schwangerschaft bei jungen Frauen mit arterieller Hypertonie verändern. Methodik Insgesamt wurden 47 Patientinnen (Alter: 25±4 Jahre) mit arterieller Hypertonie während der Schwangerschaft echokardiographisch in der 9., 24. und 33. Schwangerschaftswoche sowie 8 Wochen nach Entbindung untersucht. Als Kontrollkollektiv dienten 45 gesunde schwangere Patientinnen. Bei allen Frauen wurde der linksventrikuläre Muskelmassenindex und die systolische Durchmesserverkürzung berechnet. Folgende Doppler-echokardiographische Parameter wurden erhoben: maximale früh- und spätdiastolische Flussgeschwindigkeit, VE/VA-Quotient, Akzelerations- und Dezelerationszeit sowie isovolumetrische Relaxationszeit. Ergebnisse Im Verlauf der Schwangerschaft kam es bei allen schwangeren Frauen zu einer Zunahme des linksventrikulären Muskelmassenindex sowie zu einem Abfall der systolischen Durchmesserverkürzung. Bei allen Schwangeren entwickelten sich relevante Veränderungen der linksventrikulären diastolischen Funktionsparameter. Während das Kontrollkollektiv Kriterien einer gestörten Relaxation mit Reduktion der maximalen frühdiastolischen Flussgeschwindigkeit (von 0,89±0,07 auf 0,82±0,08 m/s*), des VE/VA Quotienten sowie einer Zunahme der isovolumetrischen Relaxationszeit (von 72±12 auf 123±7 ms*) ab der 33.Schwangerschaftswoche entwickelte (* p<0,01), zeigten sich bei den schwangeren Frauen mit arterieller Hypertonie bereits zu Beginn der Schwangerschaft die Zeichen einer gestörten Relaxation. 26 Patientinnen entwickelten ab der 24. Schwangerschaftswoche bereits ein restriktives diastolisches Füllungsmuster, während die übrigen 21 Patientinnen erst unter den Wehen und der Einleitung der Geburt kurzfristig dopplerechokardiographisch Zeichen einer diastolischen Dysfunktion im Sinne einer Restriktion entwickelten. Während die Volumenbelastung in der normalen Schwangerschaft zu einer reversiblen „physiologischen” linksventrikulären Hypertrophie, einer kurzfristigen Abnahme der systolischen Pumpfunktion kurz vor der Entbindung und einer signifikanten Adaptation der linksventrikulären diastolischen Funktion im Sinne eines gestörten Relaxationsmusters führt, konnten bei den Frauen mit arterieller frühzeitig Veränderungen im Sinne eines restriktiven Füllungsmusters dokumentiert werden. Diese Veränderungen prädisponieren zu klinischen Schwangerschaftsproblemen bei 10 von 26 Patientinnen mit arterieller Hypertonie.

Clinical and Subclinical Femoral Vascular Complications after Deployment of two Different Vascular Closure Devices or Manual Compression in the Setting of Coronary Intervention

Background: In the past two decades vascular closure devices (VCD) have been increasingly utilized as an alternative to manual compression after percutaneous femoral artery access. However, there is a lack of data confirming a significant reduction of vascular complication in a routine interventional setting. Systematic assessment of puncture sites with ultrasound was hardly performed. Methods: 620 consecutive patients undergoing elective or urgent percutaneous coronary intervention were randomly allocated to either Angioseal (AS; n = 210), or Starclose (SC; n = 196) or manual compression (MC; n = 214). As an adjunct to clinical evaluation vascular ultrasonography was used to assess the safety of each hemostatic method in terms of major and minor vascular complications. The efficacy of VCDs was assessed by achievement of puncture site hemostasis. Results: No major complications needing transfusion or vascular surgery were observed. Furthermore, the overall incidence of clinical and subclinical minor complications was similar among the three groups. There was no differences in the occurrence of pseudoaneurysmata (AS = 10; SC = 6; MC = 10), arteriovenous fistula (AS = 1; SC = 4; MC = 2) and large hematoma (AS = 11; SC = 10; MC = 14). The choice of access site treatment had no impact in the duration of hospital stay (AS = 6.7; SC = 7.4; MS = 6.4 days). Conclusions: In the setting of routine coronary intervention AS and SC provide a similar efficacy and safety as manual compression. Subclinical vascular injuries are rare and not related to VCD use.