W J Paulus

Academisch Medisch Centrum Universiteit van Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (59)517.33 Total impact

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    ABSTRACT: OBJECTIVES: To determine the prognostic value of brain natriuretic peptide (BNP) in patients with heart failure with preserved ejection fraction (HFPEF), in comparison to data in HF patients with reduced left ventricular (LV) EF (≥40%). BACKGROUND: Management of patients with HFPEF is difficult. BNP is a useful biomarker in patients with reduced LVEF, but data in HFPEF are scarce. METHODS: We studied 615 patients with mild to moderate HF (mean age 70 years, LVEF 33%), for 18 months. BNP concentrations were measured at baseline, and related to the primary outcome, i.e. a composite of all-cause mortality and HF hospitalization, and to mortality alone. The population was divided in quintiles, according to LVEF, and patients with reduced LVEF were compared to those with HFPEF. RESULTS: There were 257 patients (42%) who had a primary endpoint and 171 (28%) who died. BNP levels were significantly higher in patients with reduced LVEF than in those with HFPEF (P<0.001). BNP was a strong predictor of outcome, but LVEF was not. Importantly, if similar levels of BNP were compared across the whole spectrum of LVEF, and also for different cut-off levels of LVEF, the associated risk of adverse outcome was similar in HFPEF patients as in those with reduced LVEF. CONCLUSIONS: BNP levels are lower in HFPEF than in HF with reduced LVEF, but for a given BNP level, the prognosis in patients with HFPEF is as poor as in those with reduced LVEF.
    Journal of the American College of Cardiology 03/2013; · 14.09 Impact Factor
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    ABSTRACT: To investigate associations between baseline serum 25-hydroxyvitamin D [25(OH)D] levels and myocardial structure and function after 8 years of follow-up in older Dutch subjects. We included 256 subjects of the Hoorn Study, a population-based cohort. They underwent a standardized 2-dimensional echocardiogram at baseline between 2000 and 2001, and again between 2007 and 2009. We studied the association of 25(OH)D quartiles with echocardiographic measures of the left ventricular mass index (LVMI), left ventricular systolic function and markers of diastolic function using linear regression analyses. At baseline, subjects had a mean age of 67.4 ± 5.2 years and 41.4% had prior cardiovascular disease (CVD). Low serum 25(OH)D levels were only associated with higher LVMI at 8-year follow-up in subjects without prior CVD and in subjects with low kidney function (median estimated glomerular filtration rate ≤77.5 ml/min/1.73m(2)). The associations attenuated after adjustments for parathyroid hormone (PTH), which was associated with higher LVMI (g/m(2.7)) in subjects with low kidney function (regression coefficient highest quartile 6.3, 95% CI: 0.2, 12.5). This study showed no strong associations of 25(OH)D with myocardial structure and function. However, PTH - a possible modifiable mediator in the relation between 25(OH)D and myocardial structure - was positively associated with LVMI in subjects with low kidney function.
    Annals of Nutrition and Metabolism 01/2012; 60(1):69-77. · 1.66 Impact Factor
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    ABSTRACT: Stem cell therapy is a promising tool to improve outcome after acute myocardial infarction (AMI), but needs to be optimized since results from clinical applications remain ambiguous. A potent source of stem cells is the stromal vascular fraction of adipose tissue (SVF), which contains high numbers of adipose derived stem cells (ASC). We hypothesized that: 1) intravenous injection can be used to apply stem cells to the heart. 2) Uncultured SVF cells are easier and safer when cultured ASCs. 3) Transplantation after the acute inflammation period of AMI is favorable over early injection. For this, AMI was induced in rats by 40min of coronary occlusion. One or seven days after AMI, rats were intravenously injected with vehicle, 5×10(6) uncultured rat SVF cells or 1×10(6) rat ASCs. Rats were analyzed 35 days after AMI. Intravenous delivery of both fresh SVF cells and cultured ASCs 7 days after AMI significantly reduced infarct size compared to vehicle. Similar numbers of stem cells were found in the heart, after treatment with fresh SVF cells and cultured ASCs. Importantly, no adverse effects were found after injection of SVF cells. Using cultured ASCs, however, 3 animals had shortness of breath, and one animal died during injection. In contrast to application at 7 days post AMI, injection of SVF cells 1 day post AMI resulted in a small but non-significant infarct reduction (p=0.35). Taken together, intravenous injection of uncultured SVF cells subsequent to the acute inflammation period, is a promising stem cell therapy for AMI.
    Stem cell research 11/2011; 7(3):219-29. · 3.39 Impact Factor
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    ABSTRACT: Anecdotal cases of familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (DCM) together have been observed, suggesting that genetic factors play a role in the pathogenesis of PPCM. We hypothesized that some cases of PPCM are part of the spectrum of familial DCM, presenting in the peripartum period. We reviewed our database of 90 DCM families, focusing specifically on the presence of PPCM patients. Then, in a reverse approach, we reviewed 10 PPCM patients seen in our clinic since the early 1990s and performed cardiological screening of the first-degree relatives of 3 PPCM patients who did not show a full recovery. Finally, we analyzed the genes known to be most commonly involved in DCM in the PPCM patients. We identified a substantial number (5 of 90, 6%) of DCM families with PPCM patients. Second, cardiological screening of first-degree relatives of 3 PPCM patients who did not show full recovery revealed undiagnosed DCM in all 3 families. Finally, genetic analyses revealed a mutation (c.149A>G, p.Gln50Arg) in the gene encoding cardiac troponin C (TNNC1) segregating with disease in a DCM family with a member with PPCM, supporting the genetic nature of disease in this case. Our findings strongly suggest that a subset of PPCM is an initial manifestation of familial DCM. This may have important implications for cardiological screening in such families.
    Circulation 05/2010; 121(20):2169-75. · 15.20 Impact Factor
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    ABSTRACT: Right heart function is the main determinant of prognosis in pulmonary arterial hypertension (PAH). At present, no treatments are currently available that directly target the right ventricle, as we will demonstrate in this article. Meta-analysis of clinical trials in PAH revealed that current PAH medication seems to have limited cardiac-specific effects when analysed by the pump-function graph. Driven by the hypothesis that "left" and right heart failure might share important underlying pathophysiological mechanisms, we evaluated the clinical potential of left heart failure (LHF) therapies for PAH, based on currently available literature. As in LHF, the sympathetic nervous system and the renin-angiotension-aldosterone system are highly activated in PAH. From LHF we know that intervening in this process, e.g. by angiotensin-converting enzyme inhibition or β-blockade, is beneficial in the long run. Therefore, these medications could be also beneficial in PAH. Furthermore, the incidence of sudden cardiac death in PAH could be reduced by implantable cardioverter-defibrillators. Finally, pilot studies have demonstrated that interventricular dyssynchrony, present at end-stage PAH, responded favourably to cardiac resynchronisation therapy as well. In conclusion, therapies for LHF might be relevant for PAH. However, before they can be implemented in PAH management, safety and efficacy should be evaluated first in well-designed clinical trials.
    European Respiratory Review 03/2010; 19(115):72-82.
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    ABSTRACT: Exercise training in pulmonary arterial hypertension (PH) is a promising adjunct to medical treatment. However, it is still unclear whether training is beneficial for all PH patients. We hypothesized that right ventricular adaptation plays a pivotal role in the response to training. Two different dosages of monocrotaline were used in rats to model stable PH with preserved cardiac output and progressive PH developing right heart failure. Two weeks after injection, PH was confirmed by echocardiography, and treadmill training was initiated. Rats were trained for 4 weeks unless manifest right heart failure developed earlier. At the end of the study protocol, all rats were functionally assessed by endurance testing, echocardiography, and invasive pressure measurements. Lungs and hearts were further analyzed in quantitative histomorphologic analyses. In stable PH, exercise training was well tolerated and markedly increased exercise endurance (from 25+/-3.9 to 62+/-3.9 minutes; P<0.001). Moreover, capillary density increased significantly (from 1.21+/-0.12 to 1.51+/-0.07 capillaries per cardiomyocyte; P<0.05). However, in progressive PH, exercise training worsened survival (hazard ratio, 2.7; 95% confidence interval, 1.1 to 14.2) and increased pulmonary vascular remodeling. In addition, training induced widespread leukocyte infiltration into the right ventricle (from 135+/-14 to 276+/-18 leukocytes per 1 mm(2); P<0.001). In our rat model, exercise training was found to be beneficial in stable PH but detrimental in progressive PH. Future studies are necessary to address the clinical implications of our findings.
    Circulation 06/2009; 120(1):42-9. · 15.20 Impact Factor
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    ABSTRACT: The molecular understanding of diseases has been accelerated in recent years, producing many new potential therapeutic targets. A noninvasive delivery system that can target specific anatomical sites would be a great boost for many therapies, particularly those based on manipulation of gene expression. The use of microbubbles controlled by ultrasound as a method for delivery of drugs or genes to specific tissues is promising. It has been shown by our group and others that ultrasound increases cell membrane permeability and enhances uptake of drugs and genes. One of the important mechanisms is that microbubbles act to focus ultrasound energy by lowering the threshold for ultrasound bioeffects. Therefore, clear understanding of the bioeffects and mechanisms underlying the membrane permeability in the presence of microbubbles and ultrasound is of paramount importance. (Neth Heart J 2009;17:82-6.).
    Netherlands heart journal: monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 03/2009; 17(2):82-6. · 1.41 Impact Factor
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    ABSTRACT: In healthy human myocardium a tight balance exists between receptor-mediated kinases and phosphatases coordinating phosphorylation of regulatory proteins involved in cardiomyocyte contractility. During heart failure, when neurohumoral stimulation increases to compensate for reduced cardiac pump function, this balance is perturbed. The imbalance between kinases and phosphatases upon chronic neurohumoral stimulation is detrimental and initiates cardiac remodelling, and phosphorylation changes of regulatory proteins, which impair cardiomyocyte function. The main signalling pathway involved in enhanced cardiomyocyte contractility during increased cardiac load is the beta-adrenergic signalling route, which becomes desensitized upon chronic stimulation. At the myofilament level, activation of protein kinase A (PKA), the down-stream kinase of the beta-adrenergic receptors (beta-AR), phosphorylates troponin I, myosin binding protein C and titin, which all exert differential effects on myofilament function. As a consequence of beta-AR down-regulation and desensitization, phosphorylation of the PKA-target proteins within the cardiomyocyte may be decreased and alter myofilament function. Here we discuss involvement of altered PKA-mediated myofilament protein phosphorylation in different animal and human studies, and discuss the roles of troponin I, myosin binding protein C and titin in regulating myofilament dysfunction in cardiac disease. Data from the different animal and human studies emphasize the importance of careful biopsy procurement, and the need to investigate localization of kinases and phosphatases within the cardiomyocyte, in particular their co-localization with cardiac myofilaments upon receptor stimulation.
    Journal of Muscle Research and Cell Motility 02/2009; 29(6-8):189-201. · 1.36 Impact Factor
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    ABSTRACT: Contrast microbubbles in combination with ultrasound (US) are promising vehicles for local drug and gene delivery. However, the exact mechanisms behind intracellular delivery of therapeutic compounds remain to be resolved. We hypothesized that endocytosis and pore formation are involved during US and microbubble targeted delivery (UMTD) of therapeutic compounds. Therefore, primary endothelial cells were subjected to UMTD of fluorescent dextrans (4.4 to 500 kDa) using 1 MHz pulsed US with 0.22-MPa peak-negative pressure, during 30 seconds. Fluorescence microscopy showed homogeneous distribution of 4.4- and 70-kDa dextrans through the cytosol, and localization of 155- and 500-kDa dextrans in distinct vesicles after UMTD. After ATP depletion, reduced uptake of 4.4-kDa dextran and no uptake of 500-kDa dextran was observed after UMTD. Independently inhibiting clathrin- and caveolae-mediated endocytosis, as well as macropinocytosis significantly decreased intracellular delivery of 4.4- to 500-kDa dextrans. Furthermore, 3D fluorescence microscopy demonstrated dextran vesicles (500 kDa) to colocalize with caveolin-1 and especially clathrin. Finally, after UMTD of dextran (500 kDa) into rat femoral artery endothelium in vivo, dextran molecules were again localized in vesicles that partially colocalized with caveolin-1 and clathrin. Together, these data indicated uptake of molecules via endocytosis after UMTD. In addition to triggering endocytosis, UMTD also evoked transient pore formation, as demonstrated by the influx of calcium ions and cellular release of preloaded dextrans after US and microbubble exposure. In conclusion, these data demonstrate that endocytosis is a key mechanism in UMTD besides transient pore formation, with the contribution of endocytosis being dependent on molecular size.
    Circulation Research 02/2009; 104(5):679-87. · 11.86 Impact Factor
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    ABSTRACT: Pulmonary embolism (PE) is a significant cause of morbidity and mortality. In a recent study in patients with PE, an increased level of macrophages was found in the right ventricle. To evaluate the presence of inflammatory cells, myocytolysis and intracavitary thrombi in the left and right ventricle of patients who died because of PE as a putative new source of heart failure. 22 patients with PE were studied. For comparison, eight controls and 11 patients who died of chronic pulmonary hypertension (PHT) were used. Slides of the left and right ventricle were stained with antibodies, identifying neutrophilic granulocytes, lymphocytes and macrophages, which were subsequently quantified. Myocytolysis was visualised using complement staining. Thrombi were identified by conventional staining. Compared with controls, in patients with PE a significant increase in extravascular localisation of all three inflammatory cells was found both in the right and left ventricle, coinciding with myocytolysis, indicative for myocarditis. No increase in inflammatory cells was found in patients with PHT. Endocardial cellular infiltration was also found, partly coinciding with the presence of ventricular thrombi. In patients with PE, endomyocarditis and intracavitary thrombi in the left and right ventricle were found. These abnormalities may be an additional new explanation for the observed cardiac enzyme release and functional abnormalities of the heart in these patients and may contribute to the morbidity and mortality of the disease.
    Heart (British Cardiac Society) 05/2008; 94(4):450-6. · 5.01 Impact Factor
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    ABSTRACT: Implantable radio-telemetry methodology, allowing for continuous recording of pulmonary haemodynamics, has previously been used to assess effects of therapy on development and treatment of pulmonary hypertension. In the original procedure, rats were subjected to invasive thoracic surgery, which imposes significant stress that may disturb critical aspects of the cardiovascular system and delay recovery. In the present study, we describe and compare the original trans-thoracic approach with a new, simpler trans-diaphragm approach for catheter placement, which avoids the need for surgical invasion of the thorax. Satisfactory overall success rates up to 75% were achieved in both approaches, and right ventricular pressures and heart and respiratory rates normalised within 2 weeks. However, recovery was significantly faster in trans-diaphragm than in trans-thoracic operated animals (6.4+/-0.5 vs 9.5+/-1.1 days, respectively; p<0.05). Stable right ventricular pressures were recorded for more than 4 months, and pressure changes, induced by monocrotaline or pulmonary embolisms, were readily detected. The data demonstrate that right ventricular telemetry is a practicable procedure and a useful tool in pulmonary hypertension research in rats, especially when used in combination with echocardiography. We conclude that the described trans-diaphragm approach should be considered as the method of choice, for it is less invasive and simpler to perform.
    Pflügers Archiv - European Journal of Physiology 03/2008; 455(5):951-9. · 4.87 Impact Factor
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    ABSTRACT: Type 2 diabetes (DM2) is associated with a greater risk of heart failure. The mechanisms underlying this association remain controversial and include diabetes-associated hypertension and obesity, impaired small and large artery function, and a distinct metabolic cardiomyopathy related to hyperglycaemia/ hyperinsulinaemia. The proximate causes of heart failure are left ventricular (LV) systolic dysfunction (SDF) and diastolic dysfunction (DDF). We investigated, in a population-based cohort (n=746), the association between glucose tolerance status and SDF and DDF . The study population consisted of 274 individuals with normal glucose metabolism (NGM), 174 with impaired glucose metabolism (IGM) and 298 with DM2 (mean age 68.5 years). All participants underwent an LV echocardiogram. SDF was defined as ejection fraction <55%. DDF was determined by a sum score of peak A velocity (abnormal, >or =97 cm/s), the difference between Apv and Amv duration (> or =41 ms), and left atrial volume (> or =57 ml), where cut-off values were based upon the 90th percentile in NGM. In addition, we analysed the ratio of early to late diastolic filling (E/A ratio) on a continuous scale using linear regression analyses. The age- and sex-standardised prevalences in NGM, IGM and DM2 were 13, 14 and 30% for SDF , and 26, 36 and 47% for DDF (P trend for both <0.001). After adjustment for sex, age, hypertension, body mass index, prior cardiovascular disease and (micro) albuminuria, DM2 was significantly associated with both SDF (odds ratio (95% CI) 2.04 (1.24 to 3.36)) and DDF (2.42 (1.63 to 3.60)) (90th percentile definition). This was also true for the analyses with the E/A ratio on a continuous scale (regression coefficient b (95% CI) -0.05 (-0.09 to -0.01). After adjustment for sex, age, hypertension, body mass index, prior cardiovascular disease and (micro) albuminuria IGM was not significantly associated with SDF (odds ratio (95% CI) 1.04 (0.58 to 1.88)) or DDF (1.33 (0.86 to 2.06)) using the definition based upon the 90th percentile. However, IGM was significantly associated with DDF if the E/A ratio was analysed on a continuous scale (regression coefficient beta (95% CI) -0.05 (-0.10 to -0.01). Additional adjustment for brachial artery flow-mediated vasodilation or arterial stiffness, as measures of large artery function, did not materially alter the results. Hyperglycaemia and hyperinsulinaemia together explained approximately 30% of the association of DM2 with SDF and approximately 40% of that with DDF . DM2 is independently associated with a 2.0-fold greater risk of SDF and a 2.4-fold greater risk of DDF . IGM was not associated with SDF , and the association with DDF was limited to the E/A ratio. These observations may therefore explain the increased risk of systolic and diastolic heart failure in elderly individuals with DM2.
    The Netherlands Journal of Medicine 03/2008; 66(3):110-7. · 2.38 Impact Factor
  • Circulation 01/2008; 117(23). · 15.20 Impact Factor
  • W J Paulus, A M Shah
    Cardiovascular Research 09/1999; 43(3):595-606. · 5.94 Impact Factor
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    ABSTRACT: Patients with heart failure have modified myocardial expression of nitric oxide synthase (NOS), as is evident from induction of calcium-insensitive NOS isoforms. The functional significance of this modified NOS gene expression for left ventricular (LV) contractile performance was investigated in patients with dilated nonischemic cardiomyopathy. In patients with dilated, nonischemic cardiomyopathy, invasive measures of LV contractile performance were derived from LV microtip pressure recordings and angiograms and correlated with intensity of gene expression of inducible (NOS2) and constitutive (NOS3) NOS isoforms in simultaneously procured LV endomyocardial biopsies (n=20). LV endomyocardial expression of NOS2 was linearly correlated with LV stroke volume (P=0.001; r=0.66), LV ejection fraction (P=0.007; r=0.58), and LV stroke work (P=0.003; r=0.62). In patients with elevated LV end-diastolic pressure (>16 mm Hg), a closer correlation was observed between endomyocardial expression of NOS2 and LV stroke volume (P=0.001; r=0.74), LV ejection fraction (P=0.0007; r=0.77), and LV stroke work (r=0.82; P=0.0002). LV endomyocardial expression of NOS3 was linearly correlated with LV stroke volume (P=0.01; r=0.53) and LV stroke work (P=0.01; r=0.52). To establish the role of nitric oxide (NO) as a mediator of the observed correlations, substance P (which causes endothelial release of NO) was infused intracoronarily (n=12). In patients with elevated LV end-diastolic pressure, an intracoronary infusion of substance P increased LV stroke volume from 72+/-13 to 91+/-16 mL (P=0.06) and LV stroke work from 67+/-11 to 90+/-15 g. m (P=0.03) and shifted the LV end-diastolic pressure-volume relation to the right. In patients with dilated cardiomyopathy, an increase in endomyocardial NOS2 or NOS3 gene expression augments LV stroke volume and LV stroke work because of a NO-mediated rightward shift of the diastolic LV pressure-volume relation and a concomitant increase in LV preload reserve.
    Circulation 06/1999; 99(23):3009-16. · 15.20 Impact Factor
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    ABSTRACT: In patients with heart failure endothelium-dependent vasodilation of the forearm conduit vessels is impaired possibly because of elevated plasma levels of pro-inflammatory cytokines. The effect of elevated plasma cytokines on endothelium-dependent vasodilation of forearm conduit vessels was therefore serially investigated in 16 patients with congestive heart failure during an episode of acute failure and at the time of recompensation. Pro-inflammatory cytokine levels and hyperaemic brachial artery diameters were obtained shortly after admission for an episode of acute heart failure and 11 +/- 3 days later at the time of recompensation, which was obtained using diuretic therapy without changing other cardiovascular medications. Serum concentrations (Mean +/- SD) of tumour necrosis factor alpha (TNF-alpha) (decompensation vs recompensation: 25 +/- 23 pg.ml-1 vs 26 +/- 17 pg.ml-1) and interleukine 6 (IL-6) (decompensation vs recompensation: 27 +/- 24 pg.ml-1 vs 20 +/- 18 pg.ml-1), determined in venous blood using immunoradiometric assays were elevated but remained unaltered following recompensation. Brachial artery diameter, derived from high-resolution ultrasound scans at rest and during reactive hyperaemia, 90 s after forearm cuff deflation, increased significantly during reactive hyperaemia at the time of admission (3.4 +/- 0.7 mm vs 4.0 +/- 0.5 mm; P = 0.014) and following recompensation (3.4 +/- 0.5 mm vs 3.8 +/- 0.2 mm; P = 0.032). The brachial artery diameter during recompensation expressed as a percentage of the baseline value was similar at both intervals (decompensation vs recompensation: 117 +/- 14% vs 116 +/- 10%; P = ns). At the time of decompensation, the correlation between TNF-alpha and the percentage change in brachial artery diameter following reactive hyperaemia was absent (r = 0.098; P = 0.719). The same correlation became significant at the time of recompensation (r = 0.750; P = 0.001). In patients with congestive heart failure, plasma levels of pro-inflammatory cytokines correlate with endothelium-dependent vasodilation of the brachial artery following recompensation, but not during an acute episode of heart failure.
    European Heart Journal 06/1998; 19(5):747-52. · 14.10 Impact Factor
  • EUROPEAN HEART JOURNAL. 01/1998; 19:990-1003.
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    ABSTRACT: Myocardial expression of inducible (i) nitric oxide (NO) synthase (iNOS) gene has been reported in transplant recipients and in dilated cardiomyopathy. NO derived from NO donor or from coronary endothelium has previously been shown in the human heart to reduce end-systolic left ventricular (LV) pressure, especially during beta-adrenoreceptor stimulation, because of earlier onset of LV relaxation. The present study investigated in transplant recipients whether a similar cardiodepressant effect could be attributed to NO derived from iNOS. In 16 transplant recipients who were free of rejection or graft vasculopathy, microtip LV pressure recordings, LV angiograms, and endomyocardial biopsies were obtained at annual coronary angiography. In 8 transplant recipients, microtip LV pressure recordings were obtained during intravenous dobutamine (5 microg x kg(-1) x min(-1)). Competitive reverse transcription-polymerase chain reaction of iNOS mRNA was performed on the endomyocardial biopsies, and the intensity of iNOS mRNA expression was quantified on a scale ranging from 0 to 5+. All measures of baseline LV function were comparable in transplant recipients with low (< or = 2+) or high myocardial iNOS mRNA. During intravenous dobutamine infusion, there was a significant correlation between the abbreviation of LV electromechanical systole time (LVEST is the time from onset of QRS to dP/dt(min)) and the rise of LV dP/dt(max) (r=.79; P<.02). By use of a multiple regression analysis, addition of the intensity of iNOS mRNA expression as an independent variable significantly (P<.005) improved the correlation between deltaLVEST and deltaLV dP/dt(max) (P<.001; r=.97), implying a larger abbreviation of LV contraction for a similar rise in LV dP/dt(max), when myocardial iNOS mRNA was higher. The larger abbreviation of LV contraction in-patients with high iNOS mRNA was associated with a decrease in LV end-systolic pressure (-31+/-16 mm Hg). Myocardial iNOS gene expression in the human allograft influences the LV contractile response to beta-adrenergic stimulation through earlier onset of LV relaxation and reduction of LV end-systolic pressure. These effects are similar to the LV contractile effects of NO derived from NO donor or from coronary endothelium.
    Circulation 12/1997; 96(10):3436-42. · 15.20 Impact Factor

Publication Stats

1k Citations
517.33 Total Impact Points

Institutions

  • 2013
    • Academisch Medisch Centrum Universiteit van Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2010–2012
    • VU University Medical Center
      • Department of Physiology
      Amsterdamo, North Holland, Netherlands
  • 2009
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 1988–1999
    • OLV Ziekenhuis Aalst
      Alost, Flanders, Belgium
  • 1995–1996
    • University of Wales
      • College of Medicine
      Cardiff, Wales, United Kingdom
  • 1991
    • St. Antonius Ziekenhuis
      Nieuwegen, Utrecht, Netherlands
  • 1990
    • Ghent University
      • Department of Physiology
      Gent, VLG, Belgium