30 results on '"Vonk-Noordegraaf, Anton"'
Search Results
2. Reduced mechanical efficiency of rat papillary muscle related to degree of hypertrophy of cardiomyocytes
- Author
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Wong, Yeun Ying, Handoko, M. Louis, Mouchaers, Koen T.B., de Man, Frances S., Vonk-Noordegraaf, Anton, and van der Laarse, Willem J.
- Subjects
Hypertension -- Research ,Hypertrophy -- Research ,Papillary muscles -- Research ,Biological sciences - Abstract
Isolated rat papillary muscles of the right ventricle were used to discover the origin of reduced myocardial efficiency in chronic heart failure. Right ventricular hypertrophy was induced by monocrotaline injection, causing pulmonary hypertension. Control (n = 7) and hypertrophied (n = 11) papillary muscles were subjected to sinusoidal length changes at 37[degrees]C and 5 Hz with a peak-to-peak amplitude of 15% of the length giving maximum force ([L.sub.max]) after being stretched to 92.5% of [L.sub.max]. Isometric tension at [L.sub.max] was similar in control and hypertrophied muscles. Work was assessed from the area encompassed by force-length loops. Work per loop was 0.93 [+ or -] 0.11 and 0.84 [+ or -] 0.11 [mu]J/[mm.sup.3] (means [+ or -] SE) for control and hypertrophied muscles, respectively (P = 0.591). Suprabasal [O.sub.2] uptake per work loop was 5.7 [+ or -] 0.7 pmol/[mm.sup.3] in control muscles and 8.7 [+ or -] 1.7 pmol/[mm.sup.3] in hypertrophied muscles (P = 0.133). Net mechanical efficiency was calculated from the ratio of work output and suprabasal [O.sub.2] uptake. The efficiency of hypertrophied muscles was 29.1 [+ or -] 3.7% and was smaller than in control muscles (43.7 [+ or -] 2.2%, P = 0.016). The right ventricular cardiomyocyte cross-sectional area increased from 272 [+ or -] 17 [micro][m.sup.2] in control muscles to 396 [+ or -] 31[micro][m.sup.2.] in hypertrophied muscles (P < 0.003). Mechanical efficiency correlated negatively with right ventricular wall thickness and cardiomyocyte cross-sectional area [Spearman rank correlation coefficients of -0.50 (P = 0.039) and -0.53 (P = 0.024), respectively]. We conclude that efficiency decreases with increasing cardiomyocyte hypertrophy. Thus, the reduced efficiency of diseased whole hearts can be at least partly explained by reduced efficiency at the cardiomyocyte level. oxygen consumption; work output; monocrotaline; pulmonary hypertension; right ventricular hypertrophy doi: 10.1152/ajpheart.00773.2009.
- Published
- 2010
3. Right ventricular pacing improves right heart function in experimental pulmonary arterial hypertension: a study in the isolated heart
- Author
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Handoko, M. Louis, Lamberts, Regis R., Redout, Everaldo M., de Man, Frances S., Boer, Christa, Simonides, Warner S., Paulus, Walter J., Westerhof, Nico, Allaart, Cornelis P., and Vonk-Noordegraaf, Anton
- Subjects
Heart ventricle, Right -- Properties ,Pulmonary hypertension -- Diagnosis ,Magnetic resonance imaging -- Methods ,Cardiac pacing -- Methods ,Biological sciences - Abstract
Right heart failure in pulmonary arterial hypertension (PH) is associated with mechanical ventricular dyssynchrony, which leads to impaired right ventricular (RV) function and, by adverse diastolic interaction, to impaired left ventricular (LV) function as well. However, therapies aiming to restore synchrony by pacing are currently not available. In this proof-of-principle study, we determined the acute effects of RV pacing on ventricular dyssynchrony in PH. Chronic PH with right heart failure was induced in rats by injection of monocrotaline (80 mg/kg). To validate for PH-related ventricular dyssynchrony, rats (6 PH, 6 controls) were examined by cardiac magnetic resonance imaging (9.4 T), 23 days after monocrotaline or sham injection. In a second group (10 PH, 4 controls), the effects of RV pacing were studied in detail, using Langendorff-perfused heart preparations. In PH, septum bulging was observed, coinciding with a reversal of the transseptal pressure gradient, as observed in clinical PH. RV pacing improved RV systolic function, compared with unpaced condition (maximal first derivative of RV pressure: +8.5 [+ or -] 1.3%, P < 0.001). In addition, RV pacing markedly decreased the pressure-time integral of the transseptal pressure gradient when RV pressure exceeds LV pressure, an index of adverse diastolic interaction (-24 [+ or -] 9%, P < 0.01), and RV pacing was able to resynchronize time of RV and LV peak pressure (unpaced: 9.8 [+ or -] 1.2 ms vs. paced: 1.7 [+ or -] 2.0 ms, P < 0.001). Finally, RV pacing had no detrimental effects on LV function or coronary perfusion, and no LV preexcitation occurred. Taken together, we demonstrate that, in experimental PH, RV pacing improves RV function and diminishes adverse diastolic interaction. These findings provide a strong rationale for further in vivo explorations. right ventricular dysfunction; artificial cardiac pacing; magnetic resonance imaging; Langendorff preparation doi: 10.1152/ajpheart.00555.2009.
- Published
- 2009
4. Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension
- Author
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Mouchaers, Koen T.B., Schalij, Ingrid, Versteilen, Amanda M.G., Hadi, Awal M., van Nieuw Amerongen, Geerten P., van Hinsbergh, Victor W.M., Postmus, Pieter E., van der Laarse, Willem J., and vonk-Noordegraaf, Anton
- Subjects
Bosentan -- Physiological aspects ,Cardiovascular system -- Research ,Endothelin -- Physiological aspects ,Heart failure -- Diagnosis ,Mitochondria -- Properties ,Sildenafil -- Physiological aspects ,Biological sciences - Abstract
Pulmonary arterial hypertension (PAH) is often treated with endothelin (ET) receptor blockade or phosphodiesterase-5 (PDE5) inhibition. Little is known about the specific effects on right ventricular (RV) function and metabolism. We determined the effects of single and combination treatment with Bosentan [an ET type A ([ET.sub.A])/type B ([ET.sub.B]) receptor blocker] and Sildenafil (a PDE5 inhibitor) on RV function and oxidative metabolism in monocrotaline (MCT)-induced PAH. Fourteen days after MCT injection, male Wistar rats were orally treated for 10 days with Bosentan, Sildenafil, or both. RV catheterization and echocardiography showed that MCT clearly induced PAH. This was evidenced by increased RV systolic pressure, reduced cardiac output, increased pulmonary vascular resistance (PVR), and reduced RV fractional shortening. Quantitative histochemistry showed marked RV hypertrophy and fibrosis. Monotreatment with Bosentan or Sildenafil had no effect on RV systolic pressure or cardiac function, but RV fibrosis was reduced and RV capillarization increased. Combination treatment did not reduce RV systolic pressure, but significantly lowered PVR, and normalized cardiac output, RV fractional shortening, and fibrosis. Only combination treatment increased the mitochondrial capacity of the RV, as reflected by increased succinate dehydrogenase and cytochrome c oxidase activities, associated with an activation of PKG, as indicated by increased VASP phosphorylation. Moreover, significant interactions were found between Bosentan and Sildenafil on PVR, cardiac output, RV contractility, PKG activity, and mitochondrial capacity. These data indicate that the combination of Bosentan and Sildenafil may beneficially contribute to RV adaptation in PAH, not only by reducing PVR but also by acting on the mitochondria in the heart. Bosentan; Sildenafil; mitochondria; oxidative capacity; chronic heart failure
- Published
- 2009
5. Cardiac phase-dependent time normalization reduces load dependence of time-varying elastance
- Author
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Kind, Taco, Westerhof, Nico, Faes, Theo J.C., Lankhaar, Jan-Willem, Steendijk, Paul, and Vonk-Noordegraaf, Anton
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Heart ventricles -- Properties ,Heart beat -- Measurement ,Cardiovascular system -- Research ,Blood pressure -- Measurement ,Biological sciences - Abstract
The time-varying elastance concept provides a comprehensive description of the intrinsic mechanical properties of the left ventricle that are assumed to be load independent. Based on pressure-volume measurements obtained with combined pressure conductance catheterization in six open-chest anesthetized sheep, we show that the time to reach end systole (defined as maximal elastance) is progressively prolonged for increasing ventricle pressures, which challenges the original (load-independent) time-varying elastance concept. Therefore, we developed a method that takes into account load dependency by normalization of time course of the four cardiac phases (isovolumic contraction, ejection, isovolumic relaxation, filling) individually. With this normalization, isophase lines are obtained that connect points in pressurevolume loops of different beats at the same relative time in each of the four cardiac phases, instead of isochrones that share points at the same time in a cardiac cycle. The results demonstrate that pressure curves can be predicted with higher accuracy, if elastance curves are estimated using isophase lines instead of using isochrones [root-meansquare error (RMSE): 3.8 [+ or -] 1.0 vs. 14.0 [+ or -] 7.4 mmHg (P < 0.001), and variance accounted for (VAF): 94.8 + 1.3 vs. 78.6 [+ or -] 14.8% (P < 0.001)]. Similar results were found when the intercept volume was assumed to be time varying [RMSE: 1.7 [+ or -] 0.3 vs. 13.4 [+ or -] 7.4 mmHg (P < 0.001), and VAF: 97.4 + 0.5 vs. 81.8 [+ or -] 15.5% (P < 0.001)]. In conclusion, phase-dependent time normalization reduces cardiac load dependency of timing and increases accuracy in estimating time-varying elastance. ventricular loading; cardiac time course; isochrones; isophase lines
- Published
- 2009
6. Improved ECG detection of presence and severity of right ventricular pressure load validated with cardiac magnetic resonance imaging
- Author
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Henkens, Ivo R., Mouchaers, Koen T.B., Vonk-Noordegraaf, Anton, Boonstra, Anco, Swenne, Cees A., Maan, Arie C., Man, Sum-Che, Twisk, Jos W.R., van der Wall, Ernst E., Schalij, Martin J., and Vliegen, Hubert W.
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Electrocardiogram -- Methods ,Electrocardiography -- Methods ,Magnetic resonance imaging -- Methods ,Heart ventricle, Right -- Medical examination ,Pulmonary hypertension -- Physiological aspects ,Heart enlargement -- Physiological aspects ,Biological sciences - Abstract
The study aimed to assess whether the 12-lead ECG-derived ventricular gradient, a vectorial representation of ventricular action potential duration heterogeneity directed toward the area of shortest action potential duration, can improve ECG diagnosis of chronic right ventricular (RV) pressure load. ECGs from 72 pulmonary arterial hypertension patients recorded 1 with R > 0.5 mV in V1, and QRS axis >90[degrees]) had a sensitivity of 89% and a specificity of 93% for presence of chronic RV pressure load. However, the ventricular gradient not only had a higher diagnostic accuracy for chronic RV pressure load by receiver operating characteristic analysis [areas under the curve (AUC) = 0.993, SE 0.004 vs. AUC = 0.945, SE 0.021, P < 0.05], but also discriminated between mild-to-moderate and severe RV pressure load. CMR identified an inverse relation between the ventricular gradient and RV mass, and a trend toward a similar relation with RV volume. In conclusion, chronically increased RV pressure load is electrocardiographically reflected by an altered ventricular gradient associated with RV remodeling-related changes in ventricular action potential duration heterogeneity. The use of the ventricular gradient allows ECG detection of even mildly increased RV pressure load. hypertension; pulmonary; right ventricular hypertrophy; diagnosis; ventricular gradient; electrocardiogram
- Published
- 2008
7. Early return of reflected waves increases right ventricular wall stress in chronic thromboembolic pulmonary hypertension
- Author
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Fukumitsu, Masafumi, primary, Westerhof, Berend E., additional, Ruigrok, Dieuwertje, additional, Braams, Natalia J., additional, Groeneveldt, Joanne A., additional, Bayoumy, Ahmed A., additional, Marcus, J. Tim, additional, Meijboom, Lilian J., additional, de Man, Frances S., additional, Westerhof, Nico, additional, Bogaard, Harm-Jan, additional, and Vonk Noordegraaf, Anton, additional
- Published
- 2020
- Full Text
- View/download PDF
8. Early changes in rat hearts with developing pulmonary arterial hypertension can be detected with three-dimensional electrocardiography
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Henkens, Ivo R., Mouchaers, Koen T.B., Vliegen, Hubert W., van der Laarse, Willem J., Swenne, Cees A., Maan, Arie C., Draisma, Harmen H.M., Schalij, Ingrid, van der Wall, Ernst E., Schalij, Martin J., and Vonk-Noordegraaf, Anton
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Heart enlargement -- Physiological aspects ,Electrocardiogram -- Usage ,Electrocardiography -- Usage ,Pulmonary hypertension -- Development and progression ,Physiological research ,Biological sciences - Abstract
The study aim was to assess three-dimensional electrocardiogram (ECG) changes during development of pulmonary arterial hypertension (PAH). PAH was induced in male Wistar rats (n = 23) using monocrotaline (MCT; 40 mg/kg sc). Untreated healthy rats served as controls (n = 5). ECGs were recorded with an orthogonal three-lead system on days O, 14, and 25 and analyzed with dedicated computer software. In addition, left ventricular (LV)-to-right ventricular (RV) fractional shortening ratio was determined using echocardiography. Invasively measured RV systolic pressure was 49 (SD 10) mmHg on day 14 and 64 (SD 10) mmHg on day 25 vs. 25 (SD 2) mmHg in controls (both P < 0.001). Baseline ECGs of controls and MCT rats were similar, and ECGs of controls did not change over time. In MCT rats, ECG changes were already present on day 14 but more explicit on day 25: increased RV electromotive forces decreased mean QRS-vector magnitude and changed QRS-axis orientation. Important changes in action potential duration distribution and repolarization sequence were reflected by a decreased spatial ventricular gradient magnitude and increased QRS-T spatial angle. On day 25, LV-to-RV fractional shortening ratio was increased, and RV hypertrophy was found, but not on day 14. In conclusion, developing PAH is characterized by early ECG changes preceding RV hypertrophy, whereas severe PAH is marked by profound ECG changes associated with anatomical and functional changes in the RV. Three-dimensional ECG analysis appears to be very sensitive to early changes in RV afterload. fight ventricular hypertrophy; monocrotaline; electrocardiogram
- Published
- 2007
9. Quantification of right ventricular afterload in patients with and without pulmonary hypertension
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Lankhaar, Jan-Willem, Westerhof, Nico, Faes, Theo J.C., Marques, Koen M.J., Marcus, J. Tim, Postmus, Piet E., and Vonk-Noordegraaf, Anton
- Subjects
Heart ventricle, Right -- Research ,Pulmonary hypertension -- Physiological aspects ,Pulmonary hypertension -- Research ,Blood flow -- Research ,Biological sciences - Abstract
Right ventricular (RV) afterload is commonly defined as pulmonary vascular resistance, but this does not reflect the afterload to pulsatile flow. The purpose of this study was to quantify RV afterload more completely in patients with and without pulmonary hypertension (PH) using a three-element windkessel model. The model consists of peripheral resistance (R), pulmonary arterial compliance (C), and characteristic impedance (Z). Using pulmonary artery pressure from right-heart catheterization and pulmonary artery flow from MRI velocity quantification, we estimated the windkessel parameters in patients with chronic thromboembolic PH (CTEPH; n = 10) and idiopathic pulmonary arterial hypertension (IPAH; n = 9). Patients suspected of PH but in whom PH was not found served as controls (NONPH; n = 10). R and Z were significantly lower and C significantly higher in the NONPH group than in both the CTEPH and IPAH groups (P < 0.001). R and Z were significantly lower in the CTEPH group than in the IPAH group (P < 0.05). The parameters R and C of all patients obeyed the relationship C = 0.75/R ([R.sup.2] = 0.77), equivalent to a similar RC time in all patients. Mean pulmonary artery pressure P and C fitted well to C = 69.7/P (i.e., similar pressure dependence in all patients). Our results show that differences in RV afterload among groups with different forms of PH can be quantified with a windkessel model. Furthermore, the data suggest that the RC time and the elastic properties of the large pulmonary arteries remain unchanged in PH. pulmonary circulation; windkessel model; pulmonary blood flow; pulmonary artery pressure
- Published
- 2006
10. Impaired left ventricular filling due to right-to-left ventricular interaction in patients with pulmonary arterial hypertension
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Gan, C. Tji-Joong, Lankhaar, Jan-Willem, Marcus, J. Tim, Westerhof, Nico, Marques, Koen M., Bronzwaer, Jean G.F., Boonstra, Anco, Postmus, Pieter E., and Vonk-Noordegraaf, Anton
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Cardiac output -- Research ,Cardiac output -- Analysis ,Pulmonary circulation -- Research ,Pulmonary circulation -- Analysis ,Lungs -- Blood-vessels ,Lungs -- Research ,Lungs -- Analysis ,Biological sciences - Abstract
The aim of this study was to investigate the contribution of direct right-to-left ventricular interaction to left ventricular filling and stroke volume in 46 patients with pulmonary arterial hypertension (PAH) and 18 control subjects. Stroke volume, right and left ventricular volumes, left ventricular filling rate, and interventricular septum curvature were measured by magnetic resonance imaging and left atrial filling by transesophageal echocardiography. Stroke volume, left ventricular end-diastolic volume, and left ventricular peak filling rate were decreased in PAH patients compared with control subjects: 28 [+ or -] 13 vs. 41 [+ or -] 10 ml/[m.sup.2] (P < 0.001), 46 [+ or -] 14 vs. 61 [+ or -] 14 ml/[m.sup.2] (P < 0.001), and 216 [+ or -] 90 vs. 541 [+ or -] 248 ml/s (P < 0.001), respectively. Among PAH patients, stroke volume did not correlate to right ventricular end-diastolic volume or mean pulmonary arterial pressure but did correlate to left ventricular end-diastolic volume (r = 0.62, P < 0.001). Leftward interventricular septum curvature was correlated to left ventricular filling rate (r = 0.64, P < 0.001) and left ventricular end-diastolic volume (r = 0.65, P < 0.001). In contrast, left atrial filling was normal and not correlated to left ventricular end-diastolic volume. In PAH patients, ventricular interaction mediated by the interventricular septum impairs left ventricular filling, contributing to decreased stroke volume. ventricular interdependence; stroke volume
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- 2006
11. Right ventricular oxygen delivery as a determinant of right ventricular functional reserve during exercise in juvenile swine with chronic pulmonary hypertension
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Cai, Zongye, primary, van Duin, Richard W. B., additional, Stam, Kelly, additional, Uitterdijk, André, additional, van der Velden, Jolanda, additional, Vonk Noordegraaf, Anton, additional, Duncker, Dirk J., additional, and Merkus, Daphne, additional
- Published
- 2019
- Full Text
- View/download PDF
12. Right ventricular oxygen delivery as a determinant of right ventricular functional reserve during exercise in juvenile swine with chronic pulmonary hypertension.
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Zongye Cai, van Duin, Richard W. B., Stam, Kelly, Uitterdijk, André, van der Velden, Jolanda, Vonk Noordegraaf, Anton, Duncker, Dirk J., and Merkus, Daphne
- Abstract
Assessing right ventricular (RV) functional reserve is important for determining clinical status and prognosis in patients with pulmonary hypertension (PH). In this study, we aimed to establish RV oxygen (O
2 ) delivery as a determinant for RV functional reserve during exercise in swine with chronic PH. Chronic PH was induced by pulmonary vein banding (PVB), with sham operation serving as control. RV function and RV O2 delivery were measured over time in chronically instrumented swine, up to 12 wk after PVB at rest and during exercise. At rest, RV afterload (pulmonary artery pressure and arterial elastance) and contractility (Ees and dP/dtmax ) were higher in PH compared with control with preserved cardiac index and RV O2 delivery. However, RV functional reserve, as measured by the exercise-induced relative change (Δ) in cardiac index, dP/dtmax , and end-systolic elastance (Ees ), was decreased in PH, and RV pulmonary arterial coupling was lower both at rest and during exercise in PH. Furthermore, the increase in RV O2 delivery was attenuated in PH during exercise principally due to a lower systolic coronary blood flow in combination with an attenuated increase in aorta pressure while arterial O2 content was not significantly altered in PH. Moreover, RV O2 delivery reserve correlated with RV functional reserve, Δcardiac index (r2 = 0.85), ΔdP/dtmax (r2 = 0.49), and ΔEes (r2 = 0.70), all P < 0.05. The inability to sufficiently increase RV O2 supply to meet the increased O2 demand during exercise is principally due to the reduced RV perfusion relative to healthy control values and likely contributes to impaired RV contractile function and thereby to the limited exercise capacity that is commonly observed in patients with PH. NEW & NOTEWORTHY Impaired right ventricular (RV) O2 delivery reserve is associated with reduced RV functional reserve during exercise in a swine model of pulmonary hypertension (PH) induced by pulmonary vein banding. Our data suggest that RV function and exercise capacity might be improved by improving RV O2 delivery. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
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13. Tyrosine kinase inhibitor BIBF1000 does not hamper right ventricular pressure adaptation in rats
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de Raaf, Michiel Alexander, primary, Herrmann, Franziska Elena, additional, Schalij, Ingrid, additional, de Man, Frances S., additional, Vonk-Noordegraaf, Anton, additional, Guignabert, Christophe, additional, Wollin, Lutz, additional, and Bogaard, Harm Jan, additional
- Published
- 2016
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14. Reduced force of diaphragm muscle fibers in patients with chronic thromboembolic pulmonary hypertension
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Manders, Emmy, primary, Bonta, Peter I., additional, Kloek, Jaap J., additional, Symersky, Petr, additional, Bogaard, Harm-Jan, additional, Hooijman, Pleuni E., additional, Jasper, Jeff R., additional, Malik, Fady I., additional, Stienen, Ger J. M., additional, Vonk-Noordegraaf, Anton, additional, de Man, Frances S., additional, and Ottenheijm, Coen A. C., additional
- Published
- 2016
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15. Serotonin transporter is not required for the development of severe pulmonary hypertension in the Sugen hypoxia rat model
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de Raaf, Michiel Alexander, primary, Kroeze, Yvet, additional, Middelman, Anthonieke, additional, de Man, Frances S., additional, de Jong, Helma, additional, Vonk-Noordegraaf, Anton, additional, de Korte, Chris, additional, Voelkel, Norbert F., additional, Homberg, Judith, additional, and Bogaard, Harm Jan, additional
- Published
- 2015
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16. Diaphragm weakness in pulmonary arterial hypertension: role of sarcomeric dysfunction
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Manders, Emmy, primary, de Man, Frances S., additional, Handoko, M. L., additional, Westerhof, Nico, additional, van Hees, Hieronymus W. H., additional, Stienen, Ger J. M., additional, Vonk-Noordegraaf, Anton, additional, and Ottenheijm, Coen A. C., additional
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- 2012
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17. Impaired left ventricular filling due to right-to-left ventricular interaction in patients with pulmonary arterial hypertension
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Tji-Joong Gan, C., primary, Lankhaar, Jan-Willem, additional, Marcus, J. Tim, additional, Westerhof, Nico, additional, Marques, Koen M., additional, Bronzwaer, Jean G. F., additional, Boonstra, Anco, additional, Postmus, Pieter E., additional, and Vonk-Noordegraaf, Anton, additional
- Published
- 2006
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18. Sequential V˙a/Q˙ distributions in the normal rabbit by micropore membrane inlet mass spectrometry
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Baumgardner, James E., primary, Choi, In-Cheol, additional, Vonk-Noordegraaf, Anton, additional, Frasch, H. Frederick, additional, Neufeld, Gordon R., additional, and Marshall, Bryan E., additional
- Published
- 2000
- Full Text
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19. Reduced mechanical efficiency of rat papillary muscle related to degree of hypertrophy of cardiomyocytes.
- Author
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Yeun Ying Wong, Handoko, M. Louis, Mouchaers, Koen T. B., de Man, Frances S., Vonk-Noordegraaf, Anton, and van der Laarse, Willem J.
- Subjects
HYPERTROPHY ,HEART cells ,RIGHT heart ventricle diseases ,MONOCROTALINE ,PULMONARY hypertension ,LABORATORY rats ,HYPERTENSION risk factors - Abstract
Isolated rat papillary muscles of the right ventricle were used to discover the origin of reduced myocardial efficiency in chronic heart failure. Right ventricular hypertrophy was induced by monocrotaline injection, causing pulmonary hypertension. Control (n = 7) and hypertrophied (n = 11) papillary muscles were subjected to sinusoidal length changes at 37°C and 5 Hz with a peak-to-peak amplitude of 15% of the length giving maximum force (
L max ) after being stretched to 92.5% ofL max Isometric tension atL max was similar in control and hypertrophied muscles. Work was assessed from the area encompassed by force-length 1oops. Work per 1oop was 0.93 ± 0.11 and 0.84 ± 0.11 μJ/mm3 (means ± SE) for control and hypertrophied muscles, respectively (P = 0.591). Suprabasal O2 uptake per work loop was 5.7 ± 0.7 pmol/mm3 in control muscles and 8.7 ± 1.7 pmol/mm3 in hypertrophied muscles (P = 0.133). Net mechanical efficiency was calculated from the ratio of work output and suprabasal O2 uptake. The efficiency of hypertrophied muscles was 29.1 ± 3.7% and was smaller than in control muscles (43.7 ± 2.2%, P = 0.016). The right ventricular cardiomyocyte cross-sectional area increased from 272 ± 17 μm2 in control muscles to 396 ± 31 μm2 in hypertrophied muscles (P < 0.003). Mechanical efficiency correlated negatively with right ventricular wall thickness and cardiomyocyte cross-sectional area [Spearman rank correlation coefficients of -0.50 (P 0.039) and -0.53 (P = 0.024), respectively]. We conclude that efficiency decreases with increasing cardiomyocyte hypertrophy. Thus, the reduced efficiency of diseased whole hearts can be at least partly explained by reduced efficiency at the cardiomyocyte level. [ABSTRACT FROM AUTHOR]- Published
- 2010
- Full Text
- View/download PDF
20. Sequential ... A/... distributions in the normal rabbit by micropore membrane inlet mass spectrometry.
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BAUMGARDNER, JAMES E., CHOI, IN-CHEOL, VONK-NOORDEGRAAF, ANTON, FRASCH, H. FREDERICK, NEUFELD, GORDON R., and MARSHALL, BRYAN E.
- Published
- 2000
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21. How to incorporate tricuspid regurgitation in right ventricular-pulmonary arterial coupling.
- Author
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Yoshida K, Axelsen JB, Saku K, Andersen A, de Man FS, Sunagawa K, Vonk Noordegraaf A, and Bogaard HJ
- Abstract
Adaptation of the right ventricle (RV) to a progressively increasing afterload is one of the hallmarks of pulmonary arterial hypertension (PAH). Pressure-volume loop analysis provides measures of load-independent RV contractility, i.e., end-systolic elastance, and pulmonary vascular properties, i.e., effective arterial elastance (E
a ). However, PAH-induced RV overload potentially results in tricuspid regurgitation (TR). TR makes RV eject to both PA and right atrium; thereby, a ratio of RV end-systolic pressure (Pes ) to RV stroke volume (SV) could not correctly define Ea . To overcome this limitation, we introduced a two-parallel compliance model, i.e., Ea = 1/(1/Epa + 1/ETR ), while effective pulmonary arterial elastance (Epa = Pes /PASV) represents pulmonary vascular properties and effective tricuspid regurgitant elastance (ETR ) represents TR. We conducted animal experiments to validate this framework. First, we performed SV analysis with a pressure-volume catheter in the RV and a flow probe at the aorta in rats with and without pressure-overloaded RV to determine the effect of inferior vena cava (IVC) occlusion on TR. A discordance between the two techniques was found in rats with pressure-overloaded RV, not in sham. This discordance diminished after IVC occlusion, suggesting that TR in pressure-overloaded RV was diminished by IVC occlusion. Next, we performed pressure-volume loop analysis in rats with pressure-overloaded RVs, calibrating RV volume by cardiac magnetic resonance. We found that IVC occlusion increased Ea , suggesting that a reduction of TR increased Ea . Using the proposed framework, Epa was indistinguishable to Ea post-IVC occlusion. We conclude that the proposed framework helps better understanding of the pathophysiology of PAH and associated right heart failure. NEW & NOTEWORTHY This study reveals the impact of tricuspid regurgitation on pressure-volume loop analysis in right ventricle pressure overload. By introducing a novel concept of parallel compliances in the pressure-volume loop analysis, a better description is provided for the right ventricular forward afterload in the presence of tricuspid regurgitation.- Published
- 2023
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22. The magic of communication: the need to study organ and cell communication in pulmonary arterial hypertension-induced right heart failure.
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de Man FS and Vonk-Noordegraaf A
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- Cell Communication, Communication, Familial Primary Pulmonary Hypertension, Humans, Heart Failure etiology, Pulmonary Arterial Hypertension
- Published
- 2021
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23. Early return of reflected waves increases right ventricular wall stress in chronic thromboembolic pulmonary hypertension.
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Fukumitsu M, Westerhof BE, Ruigrok D, Braams NJ, Groeneveldt JA, Bayoumy AA, Marcus JT, Meijboom LJ, de Man FS, Westerhof N, Bogaard HJ, and Vonk Noordegraaf A
- Subjects
- Aged, Catheterization, Swan-Ganz, Chronic Disease, Female, Humans, Hypertension, Pulmonary diagnosis, Hypertension, Pulmonary physiopathology, Hypertrophy, Right Ventricular diagnostic imaging, Hypertrophy, Right Ventricular physiopathology, Magnetic Resonance Imaging, Male, Middle Aged, Pulmonary Embolism diagnosis, Pulmonary Embolism physiopathology, Retrospective Studies, Stroke Volume, Time Factors, Vascular Resistance, Ventricular Dysfunction, Right diagnostic imaging, Ventricular Dysfunction, Right physiopathology, Ventricular Remodeling, Arterial Pressure, Hypertension, Pulmonary etiology, Hypertrophy, Right Ventricular etiology, Pulmonary Artery physiopathology, Pulmonary Embolism complications, Ventricular Dysfunction, Right etiology, Ventricular Function, Right
- Abstract
Pulmonary vascular resistance (PVR) and compliance are comparable in proximal and distal chronic thromboembolic pulmonary hypertension (CTEPH). However, proximal CTEPH is associated with inferior right ventricular (RV) adaptation. Early wave reflection in proximal CTEPH may be responsible for altered RV function. The aims of the study are as follows: 1 ) to investigate whether reflected pressure returns sooner in proximal than in distal CTEPH and 2 ) to elucidate whether the timing of reflected pressure is related to RV dimensions, ejection fraction (RVEF), hypertrophy, and wall stress. Right heart catheterization and cardiac MRI were performed in 17 patients with proximal CTEPH and 17 patients with distal CTEPH. In addition to the determination of PVR, compliance, and characteristic impedance, wave separation analysis was performed to determine the magnitude and timing of the peak reflected pressure (as %systole). Findings were related to RV dimensions and time-resolved RV wall stress. Proximal CTEPH was characterized by higher RV volumes, mass, and wall stress, and lower RVEF. While PVR, compliance, and characteristic impedance were similar, proximal CTEPH was related to an earlier return of reflected pressure than distal CTEPH (proximal 53 ± 8% vs. distal 63 ± 15%, P < 0.05). The magnitude of the reflected pressure waves did not differ. RV volumes, RVEF, RV mass, and wall stress were all related to the timing of peak reflected pressure. Poor RV function in patients with proximal CTEPH is related to an early return of reflected pressure wave. PVR, compliance, and characteristic impedance do not explain the differences in RV function between proximal and distal CTEPH. NEW & NOTEWORTHY In chronic thromboembolic pulmonary hypertension (CTEPH), proximal localization of vessel obstructions is associated with poor right ventricular (RV) function compared with distal localization, though pulmonary vascular resistance, vascular compliance, characteristic impedance, and the magnitude of wave reflection are similar. In proximal CTEPH, the RV is exposed to an earlier return of the reflected wave. Early wave reflection may increase RV wall stress and compromise RV function.
- Published
- 2020
- Full Text
- View/download PDF
24. Right ventricular oxygen delivery as a determinant of right ventricular functional reserve during exercise in juvenile swine with chronic pulmonary hypertension.
- Author
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Cai Z, van Duin RWB, Stam K, Uitterdijk A, van der Velden J, Vonk Noordegraaf A, Duncker DJ, and Merkus D
- Subjects
- Age Factors, Animals, Chronic Disease, Disease Models, Animal, Female, Heart Ventricles metabolism, Hypertension, Pulmonary blood, Male, Sus scrofa, Ventricular Dysfunction, Right blood, Ventricular Pressure, Exercise Tolerance, Heart Ventricles physiopathology, Hypertension, Pulmonary physiopathology, Oxygen blood, Oxygen Consumption, Physical Exertion, Ventricular Dysfunction, Right physiopathology, Ventricular Function, Right
- Abstract
Assessing right ventricular (RV) functional reserve is important for determining clinical status and prognosis in patients with pulmonary hypertension (PH). In this study, we aimed to establish RV oxygen (O
2 ) delivery as a determinant for RV functional reserve during exercise in swine with chronic PH. Chronic PH was induced by pulmonary vein banding (PVB), with sham operation serving as control. RV function and RV O2 delivery were measured over time in chronically instrumented swine, up to 12 wk after PVB at rest and during exercise. At rest, RV afterload (pulmonary artery pressure and arterial elastance) and contractility ( Ees and dP/d tmax ) were higher in PH compared with control with preserved cardiac index and RV O2 delivery. However, RV functional reserve, as measured by the exercise-induced relative change (Δ) in cardiac index, dP/d tmax , and end-systolic elastance ( Ees ), was decreased in PH, and RV pulmonary arterial coupling was lower both at rest and during exercise in PH. Furthermore, the increase in RV O2 delivery was attenuated in PH during exercise principally due to a lower systolic coronary blood flow in combination with an attenuated increase in aorta pressure while arterial O2 content was not significantly altered in PH. Moreover, RV O2 delivery reserve correlated with RV functional reserve, Δcardiac index ( r2 = 0.85), ΔdP/d tmax ( r2 = 0.49), and Δ Ees ( r2 = 0.70), all P < 0.05. The inability to sufficiently increase RV O2 supply to meet the increased O2 demand during exercise is principally due to the reduced RV perfusion relative to healthy control values and likely contributes to impaired RV contractile function and thereby to the limited exercise capacity that is commonly observed in patients with PH. NEW & NOTEWORTHY Impaired right ventricular (RV) O2 delivery reserve is associated with reduced RV functional reserve during exercise in a swine model of pulmonary hypertension (PH) induced by pulmonary vein banding. Our data suggest that RV function and exercise capacity might be improved by improving RV O2 delivery.- Published
- 2019
- Full Text
- View/download PDF
25. Tyrosine kinase inhibitor BIBF1000 does not hamper right ventricular pressure adaptation in rats.
- Author
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de Raaf MA, Herrmann FE, Schalij I, de Man FS, Vonk-Noordegraaf A, Guignabert C, Wollin L, and Bogaard HJ
- Subjects
- Animals, Atrial Natriuretic Factor drug effects, Atrial Natriuretic Factor metabolism, Blotting, Western, Disease Models, Animal, Echocardiography, Familial Primary Pulmonary Hypertension diagnostic imaging, Familial Primary Pulmonary Hypertension metabolism, Familial Primary Pulmonary Hypertension pathology, Heart Ventricles diagnostic imaging, Heart Ventricles metabolism, Heart Ventricles pathology, Male, Mitogen-Activated Protein Kinase 1 drug effects, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 drug effects, Mitogen-Activated Protein Kinase 3 metabolism, Proto-Oncogene Proteins c-akt drug effects, Proto-Oncogene Proteins c-akt metabolism, Pulmonary Artery surgery, Rats, Rats, Sprague-Dawley, Receptors, Fibroblast Growth Factor antagonists & inhibitors, Receptors, Platelet-Derived Growth Factor antagonists & inhibitors, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors, Adaptation, Physiological drug effects, Heart Ventricles drug effects, Indoles pharmacology, Pressure, Protein Kinase Inhibitors pharmacology, Ventricular Function, Right drug effects
- Abstract
BIBF1000 is a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) and is a powerful inhibitor of fibrogenesis. BIBF1000 is very similar to BIBF1120 (nintedanib), a drug recently approved for the treatment of idiopathic pulmonary fibrosis (IPF). A safety concern pertaining to VEGFR, FGFR, and PDGFR inhibition is the possible interference with right ventricular (RV) responses to an increased afterload, which could adversely affect clinical outcome in patients with IPF who developed pulmonary hypertension. We tested the effect of BIBF1000 on the adaptation of the RV in rats subjected to mechanical pressure overload. BIBF1000 was administered for 35 days in pulmonary artery-banded (PAB) rats. RV adaptation was assessed by echocardiography, pressure volume loop analysis, histology, and determination of atrial natriuretic peptide (ANP) expression. BIBF1000 treatment resulted in growth attenuation but had no effects on RV function after PAB, given absence of changes in cardiac index, end-systolic elastance, connective tissue disposition, and capillary density. We conclude that, in this experimental model of increased afterload, combined VEGFR, FGFR, and PDGFR inhibition does not hamper RV adaptation to pressure overload., (Copyright © 2016 the American Physiological Society.)
- Published
- 2016
- Full Text
- View/download PDF
26. Reduced force of diaphragm muscle fibers in patients with chronic thromboembolic pulmonary hypertension.
- Author
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Manders E, Bonta PI, Kloek JJ, Symersky P, Bogaard HJ, Hooijman PE, Jasper JR, Malik FI, Stienen GJ, Vonk-Noordegraaf A, de Man FS, and Ottenheijm CA
- Subjects
- Aged, Calcium Signaling, Diaphragm pathology, Female, Humans, Male, Middle Aged, Muscle Contraction, Muscle Fibers, Fast-Twitch physiology, Muscle Fibers, Slow-Twitch physiology, Muscle Weakness, Pulmonary Embolism physiopathology, Diaphragm physiopathology, Hypertension, Pulmonary physiopathology
- Abstract
Patients with pulmonary hypertension (PH) suffer from inspiratory muscle weakness. However, the pathophysiology of inspiratory muscle dysfunction in PH is unknown. We hypothesized that weakness of the diaphragm, the main inspiratory muscle, is an important contributor to inspiratory muscle dysfunction in PH patients. Our objective was to combine ex vivo diaphragm muscle fiber contractility measurements with measures of in vivo inspiratory muscle function in chronic thromboembolic pulmonary hypertension (CTEPH) patients. To assess diaphragm muscle contractility, function was studied in vivo by maximum inspiratory pressure (MIP) and ex vivo in diaphragm biopsies of the same CTEPH patients (N = 13) obtained during pulmonary endarterectomy. Patients undergoing elective lung surgery served as controls (N = 15). Muscle fiber cross-sectional area (CSA) was determined in cryosections and contractility in permeabilized muscle fibers. Diaphragm muscle fiber CSA was not significantly different between control and CTEPH patients in both slow-twitch and fast-twitch fibers. Maximal force-generating capacity was significantly lower in slow-twitch muscle fibers of CTEPH patients, whereas no difference was observed in fast-twitch muscle fibers. The maximal force of diaphragm muscle fibers correlated significantly with MIP. The calcium sensitivity of force generation was significantly reduced in fast-twitch muscle fibers of CTEPH patients, resulting in a ∼40% reduction of submaximal force generation. The fast skeletal troponin activator CK-2066260 (5 μM) restored submaximal force generation to levels exceeding those observed in control subjects. In conclusion, diaphragm muscle fiber contractility is hampered in CTEPH patients and contributes to the reduced function of the inspiratory muscles in CTEPH patients., (Copyright © 2016 the American Physiological Society.)
- Published
- 2016
- Full Text
- View/download PDF
27. Serotonin transporter is not required for the development of severe pulmonary hypertension in the Sugen hypoxia rat model.
- Author
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de Raaf MA, Kroeze Y, Middelman A, de Man FS, de Jong H, Vonk-Noordegraaf A, de Korte C, Voelkel NF, Homberg J, and Bogaard HJ
- Subjects
- Animals, Cell Hypoxia, Gene Knockout Techniques, Hypertension, Pulmonary pathology, Hypertension, Pulmonary physiopathology, Lung blood supply, Lung metabolism, Lung pathology, Male, Proliferating Cell Nuclear Antigen metabolism, Rats, Vascular Remodeling, Hypertension, Pulmonary metabolism, Serotonin Plasma Membrane Transport Proteins physiology
- Abstract
Increased serotonin serum levels have been proposed to play a key role in pulmonary arterial hypertension (PAH) by regulating vessel tone and vascular smooth muscle cell proliferation. An intact serotonin system, which critically depends on a normal function of the serotonin transporter (SERT), is required for the development of experimental pulmonary hypertension in rodents exposed to hypoxia or monocrotaline. While these animal models resemble human PAH only with respect to vascular media remodeling, we hypothesized that SERT is likewise required for the presence of lumen-obliterating intima remodeling, a hallmark of human PAH reproduced in the Sugen hypoxia (SuHx) rat model of severe angioproliferative pulmonary hypertension. Therefore, SERT wild-type (WT) and knockout (KO) rats were exposed to the SuHx protocol. SERT KO rats, while completely lacking SERT, were hemodynamically indistinguishable from WT rats. After exposure to SuHx, similar degrees of severe angioproliferative pulmonary hypertension and right ventricular hypertrophy developed in WT and KO rats (right ventricular systolic pressure 60 vs. 55 mmHg, intima thickness 38 vs. 30%, respectively). In conclusion, despite its implicated importance in PAH, SERT does not play an essential role in the pathogenesis of severe angioobliterative pulmonary hypertension in rats exposed to SuHx., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
- Full Text
- View/download PDF
28. Diaphragm weakness in pulmonary arterial hypertension: role of sarcomeric dysfunction.
- Author
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Manders E, de Man FS, Handoko ML, Westerhof N, van Hees HW, Stienen GJ, Vonk-Noordegraaf A, and Ottenheijm CA
- Subjects
- Animals, Calcium pharmacology, Diaphragm drug effects, Familial Primary Pulmonary Hypertension, Hypertension, Pulmonary chemically induced, Male, Monocrotaline toxicity, Muscle Contraction drug effects, Muscle Contraction physiology, Muscle Fibers, Skeletal drug effects, Muscle Fibers, Skeletal physiology, Muscle Weakness chemically induced, Myosin Heavy Chains analysis, Myosin Heavy Chains physiology, Rats, Rats, Wistar, Sarcomeres drug effects, Diaphragm physiopathology, Hypertension, Pulmonary physiopathology, Muscle Weakness physiopathology, Sarcomeres physiology
- Abstract
We previously demonstrated that diaphragm muscle weakness is present in experimental pulmonary arterial hypertension (PH). However, the nature of this diaphragm weakness is still unknown. Therefore, the aim of this study was to investigate whether changes at the sarcomeric level contribute to diaphragm weakness in PH. For this purpose, in control rats and rats with monocrotaline-induced PH, contractile performance and myosin heavy chain content of demembranated single diaphragm fibers were determined. We observed a reduced maximal tension of 20% (P < 0.05), whereas tension cost was preserved in type 2X and 2B diaphragm fibers in PH compared with control. The reduced maximal tension was associated with a reduction of force generated per half-sarcomeric myosin heavy chain content. Additionally, reduced Ca(2+) sensitivity of force generation was found in type 2X fibers compared with control, which could exacerbate diaphragm muscle weakness at submaximal activation. No changes in maximal tension and Ca(2+) sensitivity of force generation were observed in fibers from the nonrespiratory extensor digitorum longus muscle. Together, these findings indicate that diaphragm weakness in PH is at least partly caused by sarcomeric dysfunction, which appears to be specific for the diaphragm.
- Published
- 2012
- Full Text
- View/download PDF
29. Aortic function quantified: the heart's essential cushion.
- Author
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Saouti N, Marcus JT, Vonk Noordegraaf A, and Westerhof N
- Subjects
- Adult, Aging physiology, Cardiovascular Diseases physiopathology, Compliance physiology, Diastole physiology, Female, Humans, Magnetic Resonance Imaging methods, Male, Pulse Wave Analysis methods, Regional Blood Flow physiology, Systole physiology, Young Adult, Aorta physiology, Blood Pressure physiology, Heart physiology
- Abstract
Arterial compliance is mainly determined by the elasticity of proximal large-conduit arteries of which the aorta is the largest contributor. Compliance forms an important part of the cardiac load and plays a role in organ (especially coronary) perfusion. To follow local changes in aortic compliance, as in aging, noninvasive determination of compliance distribution would be of great value. Our goal is to determine regional aortic compliance noninvasively in the human. In seven healthy individuals at six locations, aortic blood flow and systolic/diastolic area (ΔA) was measured with MRI. Simultaneously brachial pulse pressure (ΔP) was measured with standard cuff. With a transfer function we derived ΔP at the same aortic locations as the MRI measurements. Regional aortic compliance was calculated with two approaches, the pulse pressure method, and local area compliance (ΔA/ΔP) times segment length, called area compliance method. For comparison, pulse wave velocity (PWV) from local flows at two locations was determined, and compliance was derived from PWV. Both approaches show that compliance is largest in the proximal aorta and decreases toward the distal aorta. Similar results were found with PWV-derived compliance. Of total arterial compliance, ascending to distal arch (segments 1-3) contributes 40% (of which 15% is in head and arms), descending aorta (segments 4 and 5) 25%, and "hip, pelvic and leg arteries" 20%. Pulse pressure method includes compliance of side branches and is therefore larger than the area compliance method. Regional aortic compliance can be obtained noninvasively. Therefore, this technique allows following changes in local compliance with age and cardiovascular diseases.
- Published
- 2012
- Full Text
- View/download PDF
30. A computed method for noninvasive MRI assessment of pulmonary arterial hypertension.
- Author
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Lankhaar JW, Vonk Noordegraaf A, and Marcus JT
- Subjects
- Humans, Hypertension, Pulmonary pathology, Image Processing, Computer-Assisted methods, Magnetic Resonance Imaging methods
- Published
- 2004
- Full Text
- View/download PDF
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