| 1. |
- Maksuti, Elira, et al.
(författare)
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Cardiac remodeling in aortic and mitral valve disease : a simulation study with clinical validation
- 2019
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Ingår i: Journal of Applied Physiology. - Stockholm : Karolinska Institutet, Dept of Physiology and Pharmacology. - 8750-7587 .- 1522-1601.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Remodeling is an important long-term determinant of cardiac function throughout the progression of heart disease. Numerous biomolecular pathways for mechanosensing and transduction are involved. However, we hypothesize that biomechanical factors alone can explain changes in myocardial volume and chamber size in valve disease. Methods: A validated model of the human vasculature and the four cardiac chambers was used to simulate aortic stenosis, mitral regurgitation and aortic regurgitation. Remodeling was simulated with adaptive feedback preserving myocardial fiber stress and wall shear stress in all four cardiac chambers. Briefly, the model used myocardial fiber stress to determine wall thickness and cardiac chamber wall shear stress to determine chamber volume. Results: Aortic stenosis resulted in the development of concentric left ventricular hypertrophy. Aortic and mitral regurgitation resulted in eccentric remodeling and eccentric hypertrophy, with more pronounced hypertrophy for aortic regurgitation. Comparisons with published clinical data showed the same direction and similar magnitudes of changes in end-diastolic volume index and left ventricular diameters. Changes in myocardial wall volume and wall thickness were within a realistic range both in stenotic and regurgitant valvular disease. Conclusions: Simulations of remodeling in left-sided valvular disease support, in both a qualitative and quantitative manner, that left ventricular chamber size and hypertrophy are primarily determined by preservation of wall shear stress and myocardial fiber stress.
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| 2. |
- Ahlborg, G, et al.
(författare)
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Central and regional hemodynamic effects during infusion of Big endothelin-1 in healthy humans
- 1996
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Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 80:6, s. 1921-1927
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Tidskriftsartikel (refereegranskat)abstract
- Big endothelin-1 (Big ET-1) was given intravenously to six healthy men to study uptakes and vascular effects. Blood samples were taken from systemic and pulmonary arterial and internal jugular and deep forearm venous catheters. Arterial Big ET-1-like immunoreactivity (Big ET-1-LI) increased from 5.43 +/- 0.60 to 756 +/- 27 pmol/l, and ET-1-LI increased from 4.67 +/- 0.08 to 6.67 +/- 0.52 pmol/l (P < 0.001). Skeletal muscle fractional extraction of Big ET-1-LI was 15 +/- 4%. ET-1-LI release did not increase in the studied vascular beds. Heart rate fell by 17% (P < 0.001), cardiac output fell by 26% (P < 0.001), and stroke volume fell by 11% (P < 0.05). Mean arterial blood pressure increased 18%, systemic vascular resistance increased 65%, and pulmonary vascular resistance increased 57% (P < 0.01-0.001). Pulmonary blood pressures, forearm blood flow, arterial pH, arterial PCO2, and systemic arterial-internal jugular venous O2 difference remained unchanged. No specific Big ET-1 receptors were found in human pulmonary membranes. The half-maximal inhibitory concentration for the receptor antagonist bosentan was 181 nM. In summary, circulating Big ET-1 elicits greater increases in mean arterial blood pressure and systemic vascular resistance and decreases in heart rate and cardiac output compared with an equimolar ET-1 infusion (26).
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| 3. |
- AHLBORG, G, et al.
(författare)
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Circulating endothelin-1 reduces splanchnic and renal blood flow and splanchnic glucose production in humans
- 1995
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Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 79:1, s. 141-145
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Tidskriftsartikel (refereegranskat)abstract
- The effect of minimal changes in circulating plasma endothelin-1 (ET-1) was studied in 12 healthy subjects receiving either 60 min of ET-1 (0.2 pmol.kg-1.min-1) or physiological saline intravenously. Blood was drawn from arterial, renal, and central hepatic vein catheters. Arterial ET-1-like immunoreactivity (ET-1-LI) increased from 4.7 +/- 0.4 (SE) to 8.6 +/- 1.0 pmol/l during ET-1 infusion. After 10 min, plasma ET-1-LI had increased to 6.12 +/- 0.29 pmol/l. For comparison the plasma ET-1-LI level was 12.9 +/- 4.2 pmol/in five patients with sepsis syndrome. Mean arterial blood pressure rose from 92 +/- 3 to 99 +/- 4 mmHg. Estimated splanchnic and renal blood flows fell by 18 +/- 5 and 10 +/- 3%, respectively, and splanchnic glucose production fell by 42 +/- 6% within 10 min of the ET-1 infusion and differed compared with corresponding control values. Only estimated splanchnic blood flow had increased 60 min after the ET-1 infusion. No change in splanchnic uptake of lactate or glycerol was seen. In conclusion, we suggest that circulating ET-1 with small or no demonstrable change in plasma concentration interferes with vasoactivity and splanchnic glycogenolyses in health and possibly pathophysiological conditions.
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| 4. |
- Ahlborg, G, et al.
(författare)
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Insulin sensitivity and big ET-1 conversion to ET-1 after ETA- or ETB-receptor blockade in humans
- 2002
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Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 93:6, s. 2112-2121
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Tidskriftsartikel (refereegranskat)abstract
- Cardiovascular diseases are characterized by insulin resistance and elevated endothelin (ET)-1 levels. Furthermore, ET-1 induces insulin resistance. To elucidate this mechanism, six healthy subjects were studied during a hyperinsulinemic euglycemic clamp during infusion of (the ET-1 precursor) big ET-1 alone or after ETA- or ETB-receptor blockade. Insulin levels rose after big ET-1 with or without the ETB antagonist BQ-788 ( P < 0.05) but were unchanged after the ETA antagonist BQ-123 + big ET-1. Infused glucose divided by insulin fell after big ET-1 with or without BQ-788 ( P < 0.05). Insulin and infused glucose divided by insulin values were normalized by ETA blockade. Mean arterial blood pressure rose during big ET-1 with or without BQ-788 ( P < 0.001) but was unchanged after BQ-123. Skeletal muscle, splanchnic, and renal blood flow responses to big ET-1 were abolished by BQ-123. ET-1 levels rose after big ET-1 ( P< 0.01) in a similar way after BQ-123 or BQ-788, despite higher elimination capacity after ETA blockade. In conclusion, ET-1-induced reduction in insulin sensitivity and clearance as well as splanchnic and renal vasoconstriction are ETA mediated. ETA-receptor stimulation seems to inhibit the conversion of big ET-1 to ET-1.
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| 5. |
- AHLBORG, G, et al.
(författare)
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Metabolic and vascular effects of circulating endothelin-1 during moderately heavy prolonged exercise
- 1995
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Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 78:6, s. 2294-2300
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Tidskriftsartikel (refereegranskat)abstract
- The aims were to investigate 1) the effects of endothelin-1 (ET-1) during exercise and 2) the influence of exercise on arterial ET-1 levels. Six healthy subjects performed two exercises of 2 h duration at 50% of peak oxygen uptake preceded by intravenous infusion of physiological saline or ET-1 (4 pmol.kg-1.min-1). Blood specimens were taken from arterial and hepatic vein catheters. Arterial ET-1 rose 15-fold during the infusion. Splanchnic blood flow fell after ET-1 and remained lower than in control subjects during exercise (P < 0.001). Splanchnic glucose production was approximately 25% lower compared with control values during the whole exercise period (P < 0.01). Neither heart rate, arterial glucagon, insulin, catecholamines, renin, glucose, lactate, nor glycerol levels differed from control exercise values. The calculated gluconeogenesis from glycerol and lactate did not differ from the control values. ET-1 levels rose approximately twofold in the control exercise (P < 0.01) and in another group of seven subjects performing 1 h of exercise at 70% of peak oxygen uptake (P < 0.001). In conclusion, ET-1 levels increased during exercise without ET-1 administration. In addition, circulating ET-1 has a (direct or indirect) regulatory action on splanchnic blood flow and glucose metabolism during exercise (and possibly under pathophysiological conditions) in humans.
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| 6. |
- Ahlborg, G, et al.
(författare)
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Nitric oxide-endothelin-1 interaction in humans
- 1997
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Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 82:5, s. 1593-1600
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Tidskriftsartikel (refereegranskat)abstract
- Ahlborg, Gunvor, and Jan M. Lundberg. Nitric oxide–endothelin-1 interaction in humans. J. Appl. Physiol. 82(5): 1593–1600, 1997.—Healthy men received NG-monomethyl-l-arginine (l-NMMA) intravenously to study cardiovascular and metabolic effects of nitric oxide synthase blockade and whether this alters the response to endothelin-1 (ET-1) infusion. Controls only received ET-1.l-NMMA effects were that heart rate (17%), cardiac output (17%), and splanchnic and renal blood flow (both 33%) fell promptly (all P < 0.01). Mean arterial blood pressure (6%), and systemic (28%) and pulmonary (40%) vascular resistances increased ( P < 0.05 to 0.001). Arterial ET-1 levels (21%) increased due to a pulmonary net ET-1 release ( P < 0.05 to 0.01). Splanchnic glucose output (SGO) fell (26%, P < 0.01). Arterial insulin and glucagon were unchanged. Subsequent ET-1 infusion caused no change in mean arterial pressure, heart rate, or cardiac output, as found in the present controls, or in splanchnic and renal blood flow or splanchnic glucose output as previously found with ET-1 infusion (G. Ahlborg, E. Weitzberg, and J. M. Lundberg. J. Appl. Physiol. 79: 141–145, 1995). In conclusion, l-NMMA like ET-1, induces prolonged cardiovascular effects and suppresses SGO.l-NMMA causes pulmonary ET-1 release and blocks responses to ET-1 infusion. The results indicate that nitric oxide inhibits ET-1 production and thereby interacts with ET-1 regarding increase in vascular tone and reduction of SGO in humans.
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| 7. |
- Ahmed, AS, et al.
(författare)
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Type 2 diabetes impairs tendon repair after injury in a rat model
- 2012
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Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 113:11, s. 1784-1791
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes adversely affects the properties of native connective tissue. The underlying mechanisms, however, by which diabetes alters connective tissue metabolism, especially tendon, are poorly defined. The aim of this study was to determine the effect of type 2 diabetes on the mechanical, histological, and molecular properties of the intact and healing Achilles tendon. The right Achilles tendon was transected in 11 male diabetic Goto-Kakizaki (GK) and 10 age- and sex-matched Wistar control rats, while the left Achilles tendon was left intact. At 2 wk postinjury the intact and injured tendons were assessed by biomechanical testing and histology. The gene expression of collagen I and III, biglycan, versican, MMP-13, and MMP-3 was measured by quantitative RT-PCR, and their protein distribution was studied by immunohistochemistry. Intact tendons exhibited only small differences between the groups. In injured tendons, however, a significantly smaller transverse area and lower stiffness was found in diabetic GK compared with Wistar control rats. This correlated with impaired structural organization of collagen fibers and a reduced expression of collagen I and III in the injured tendons of the diabetic GK compared with Wistar control. Moreover, MMP-3 gene expression was downregulated in the injured diabetic GK tendons compared with injured Wistar controls. Our results indicate that in a rat model of diabetes tendon healing is impaired mainly due to altered expression of collagen and MMPs reflecting decreased degradation of matrix proteins and impaired tissue remodeling. Further our data suggest that therapeutic modulation of collagens or MMPs might be targets for new regenerative approaches in operated, injured, or maybe also degenerative tendon diseases in diabetes.
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| 8. |
- Al-Mashat, Mariam, et al.
(författare)
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Increased pulmonary blood volume variation in patients with heart failure compared to healthy controls; a non-invasive, quantitative measure of heart failure
- 2020
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Ingår i: Journal of Applied Physiology. - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 128:2, s. 324-337
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Tidskriftsartikel (refereegranskat)abstract
- Variation of the blood content of the pulmonary vascular bed during a heartbeat can be quantified by pulmonary blood volume variation (PBVV) using magnetic resonance imaging (MRI). The aim was to evaluate if PBVV differs in patients with heart failure compared to healthy controls and investigate the mechanisms behind the PBVV. Forty-six patients and 10 controls underwent MRI. PBVV was calculated from blood flow measurements in the main pulmonary artery and a pulmonary vein, defined as the maximum difference in cumulative PBV over one heartbeat. PBVV was indexed to stroke volume (SV) in the main pulmonary artery (PBVVSV). Patients displayed higher PBVVSV than controls (58±14% vs 43±7%, p<0.001). The change in PBVVSV could be explained by left ventricular (LV) longitudinal contribution to SV (R2=0.15, p=0.02) and the phase shift between in- and outflow (R2=0.31, p<0.001) in patients. Both variables contributed to the multiple regression analysis model and predicted PBVVSV (R2=0.38), however, the phase shift alone explained about ~30% of the variation in PBVVSV. No correlation was found between PBVVSV and large vessel area. In conclusion, PBVVSV was higher in patients compared to controls. Approximately 40% of the variation of PBVVSV in patients can be explained by the LV longitudinal contribution to SV and the phase shift between pulmonary in- and outflow, where the phase shift alone accounts for ~30%. The remaining variation, (60-70%), most likely occurs on small vessel level. Future studies are needed to show the clinical added value of PBVVSV compared to right heart catheterization.
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| 9. |
- Allen, DG, et al.
(författare)
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Impaired calcium release during fatigue
- 2008
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Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 104:1, s. 296-305
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Tidskriftsartikel (refereegranskat)abstract
- Impaired calcium release from the sarcoplasmic reticulum (SR) has been identified as a contributor to fatigue in isolated skeletal muscle fibers. The functional importance of this phenomenon can be quantified by the use of agents, such as caffeine, which can increase SR Ca2+release during fatigue. A number of possible mechanisms for impaired calcium release have been proposed. These include reduction in the amplitude of the action potential, potentially caused by extracellular K+accumulation, which may reduce voltage sensor activation but is counteracted by a number of mechanisms in intact animals. Reduced effectiveness of SR Ca2+channel opening is caused by the fall in intracellular ATP and the rise in Mg2+concentrations that occur during fatigue. Reduced Ca2+available for release within the SR can occur if inorganic phosphate enters the SR and precipitates with Ca2+. Further progress requires the development of methods that can identify impaired SR Ca2+release in intact, blood-perfused muscles and that can distinguish between the various mechanisms proposed.
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| 10. |
- Allen, G, et al.
(författare)
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Transient mechanical benefits of a deep inflation in the injured mouse lung
- 2002
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Ingår i: Journal of Applied Physiology. - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 93:5, s. 1709-1715
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Tidskriftsartikel (refereegranskat)abstract
- The lasting effects of a recruitment maneuver (RM) in the injured lung are not well characterized. We speculated that the reduction in respiratory elastance (H) after a deep inflation (DI) is transient in nature and should be sustained longer at higher positive end-expiratory pressure (PEEP). Thirteen ventilated mice were given 2 DIs at various levels of PEEP before and after saline lavage. Forced oscillations were used to measure H periodically over 7 min after the DIs. Time constants (tau) were estimated for the post-DI recovery in H. Values for tau before lavage (80-115 s) were reduced after lavage (13-30 s) at all levels of PEEP (P = 0.0001). PEEP did not significantly influence tau before or after lavage. The plateau level and total recovery in H after a DI were significantly influenced by PEEP and lavage (P < 0.0001). Our results suggest that for a DI to be beneficial in the injured mouse lung, it may have to be applied several times a minute.
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