| 1. |
- Perman, Jeanna, 1981, et al.
(författare)
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The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction.
- 2011
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Ingår i: The Journal of clinical investigation. - : American Society for Clinical Investigation. - 1558-8238 .- 0021-9738. ; 121:7, s. 2625-40
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Tidskriftsartikel (refereegranskat)abstract
- Impaired cardiac function is associated with myocardial triglyceride accumulation, but it is not clear how the lipids accumulate or whether this accumulation is detrimental. Here we show that hypoxia/ischemia-induced accumulation of lipids in HL-1 cardiomyocytes and mouse hearts is dependent on expression of the VLDL receptor (VLDLR). Hypoxia-induced VLDLR expression in HL-1 cells was dependent on HIF-1α through its interaction with a hypoxia-responsive element in the Vldlr promoter, and VLDLR promoted the endocytosis of lipoproteins. Furthermore, VLDLR expression was higher in ischemic compared with nonischemic left ventricles from human hearts and was correlated with the total lipid droplet area in the cardiomyocytes. Importantly, Vldlr-/- mice showed improved survival and decreased infarct area following an induced myocardial infarction. ER stress, which leads to apoptosis, is known to be involved in ischemic heart disease. We found that ischemia-induced ER stress and apoptosis in mouse hearts were reduced in Vldlr-/- mice and in mice treated with antibodies specific for VLDLR. These findings suggest that VLDLR-induced lipid accumulation in the ischemic heart worsens survival by increasing ER stress and apoptosis.
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| 2. |
- Andersson, Bert, 1952, et al.
(författare)
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Dose-related effects of metoprolol on heart rate and pharmacokinetics in heart failure.
- 2001
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Ingår i: Journal of cardiac failure. - 1071-9164. ; 7:4, s. 311-7
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacokinetics and pharmacodynamics of immediate-release (IR) metoprolol, 50 mg 3 times daily, were compared with those of different doses of controlled-release/extended-release metoprolol (CR/XL) given once daily.Fifteen patients with chronic heart failure were randomized to a 3-way crossover study to receive metoprolol IR 50 mg 3 times daily, CR/XL 100 mg once daily, and CR/XL 200 mg once daily for 7 days. On the seventh day of each treatment, serial plasma samples were drawn and standardized exercise tests and a 24-hour Holter recording were performed. Metoprolol IR 50 mg produced peak plasma levels comparable to those observed for CR/XL 200 mg (285 v 263 nmol/L). The difference in mean 24-hour heart rate between CR/XL 100 mg and IR 50 mg was 1.0 bpm (95% confidence interval [CI]), -2.9 to 4.9; NS) compared with -3.8 bpm (95% CI, -7.6 to -0.04; P = .048) between CR/XL 200 mg and IR 50 mg. Submaximal exercise heart rate was lower for patients receiving CR/XL 200 mg than those receiving IR 50 mg. No difference in tolerance or exercise performance was observed between treatment regimens.Peak plasma levels produced by metoprolol 200 mg CR/XL were similar to those of 50 mg IR. Metoprolol CR/XL 200 mg was associated with a more pronounced suppression of heart rate than metoprolol IR 50 mg. It is suggested that patients can safely be switched from multiple dosing of metoprolol IR 50 mg to a once-daily dose of metoprolol CR/XL.
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| 3. |
- Andersson, Bert, 1952, et al.
(författare)
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Early changes in longitudinal performance predict future improvement in global left ventricular function during long term beta adrenergic blockade.
- 2000
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Ingår i: Heart (British Cardiac Society). - 1468-201X. ; 84:6, s. 599-605
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Tidskriftsartikel (refereegranskat)abstract
- Contraction of longitudinal and subendocardial myocardial muscle fibres is reflected in descent of the atrioventricular (AV) plane. The aim was therefore to determine whether beta blocker treatment with prolongation of diastole might result in improved function as reflected by AV plane movements in patients with chronic heart failure.Double blind, randomised, placebo controlled and open intervention study.University hospital.Patients with congestive heart failure: placebo controlled (n = 26) and an open protocol (n = 15).12 months of metoprolol treatment.Short axis and long axis echocardiography, invasive haemodynamics, radionuclide angiography.Recovery of systolic and diastolic function during metoprolol treatment was reflected by early changes in mean (SD) AV plane amplitude, from 5.3 (2.0)% to 7.1 (3.2)% and 7.8 (3. 1)% (at 3 and 12 months, respectively; p < 0.05). In a multivariate analysis, only the change in AV plane amplitude by three months was independently associated with improvement in pulmonary capillary wedge pressure by six months (r = 0.80, p = 0.017). Change in AV plane amplitude by three months was also a better predictor of improvement in ejection fraction by 12 months (r = 0.78, p < 0.001) than changes in radionuclide ejection fraction by three months (r = 0.34, p = 0.049).Improvement in longitudinal contraction was closely associated with a decrease in left ventricular filling pressure during metoprolol treatment. This association was stronger than changes in short axis performance or radionuclide ejection fraction, emphasising the importance of AV plane motion for left ventricular filling and systolic performance in patients with heart failure.
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| 4. |
- Andersson, Bert, 1952, et al.
(författare)
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Longitudinal myocardial contraction improves early during titration with metoprolol CR/XL in patients with heart failure.
- 2002
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Ingår i: Heart (British Cardiac Society). - 1468-201X. ; 87:1, s. 23-8
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Tidskriftsartikel (refereegranskat)abstract
- To investigate diastolic and systolic left ventricular recovery during titration with metoprolol CR/XL (controlled release/extended release).Placebo run in, followed by an open study.University hospital.14 patients with chronic heart failure.Metoprolol CR/XL titrated from 12.5 mg once daily to 200 mg once daily.M mode recordings of atrioventricular (AV) plane displacement, Doppler measurement of transmitral flow and pulmonary venous flow, two dimensional ejection fraction, and measurement of venous plasma concentration of noradrenaline. Patients were investigated after 2, 4, 6, and 24 weeks of treatment.A reduction of heart rate was observed on the first dose (12.5 mg once daily), from a mean (SD) of 74 (11) to 67 (11) beats/min, p < 0.05. This was accompanied by prominent effects on AV plane filling parameters, including an increase in early diastolic filling period from 87 (28) to 105 (33) ms (p < 0.05), and in the lateral AV plane fractional shortening from 8.7 (2.7)% to 10.2 (2.8)% (p < 0.05). An early trend towards improvement in global systolic left ventricular function was also seen, although this was not significant until six weeks. Ejection fraction increased from 33 (7.5)% to 38 (11)% (p < 0.05).First effects of left ventricular recovery during beta blocker treatment were seen in recordings of longitudinal performance, as expressed by AV plane displacement. Doppler flow dynamics as well as global systolic recovery appeared several weeks later, emphasising the importance of longitudinal performance in evaluating left ventricular function.
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| 5. |
- Andersson, Linda, 1973, et al.
(författare)
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Rip2 modifies VEGF-induced signalling and vascular permeability in myocardial ischemia
- 2015
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 107:4, s. 478-486
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Tidskriftsartikel (refereegranskat)abstract
- In myocardial ischemia, vascular endothelial growth factor (VEGF) induces permeability by activating a signalling pathway that includes VEGF receptor 2 (VEGFR2), resulting in increased oedema and inflammation and thereby expanding the area of tissue damage. In this study, we investigated the role of receptor-interacting protein 2 (Rip2) in VEGF signalling and myocardial ischemia/reperfusion injury.
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| 6. |
- Bollano, Entela, 1970, et al.
(författare)
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Different responses to dobutamine in the presence of carvedilol or metoprolol in patients with chronic heart failure.
- 2003
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Ingår i: Heart (British Cardiac Society). - 1468-201X. ; 89:6, s. 621-4
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Tidskriftsartikel (refereegranskat)abstract
- To determine whether patients with congestive heart failure on different beta adrenoreceptor blocking drugs have similar haemodynamic responses to dobutamine.Single centre, single blind, randomised, two period crossover study comparing carvedilol with metoprolol CR/XL.Ten patients with stable chronic congestive heart failure (ejection fraction < 40%) on chronic treatment with metoprolol CR/XL.Patients were treated with carvedilol or metoprolol CR/XL (target dose 50 mg twice daily and 200 mg once daily, respectively) for eight weeks. Stress echocardiography was undertaken at the end of each maintenance period, using dobutamine 5 and 15 microg/kg/min.No significant haemodynamic differences were seen at rest on the two treatments. There was a more pronounced increase in heart rate and cardiac output during dobutamine infusion when the patients were on metoprolol than when they were on carvedilol. Mean arterial pressure increased significantly when the patients were on carvedilol, and cardiac output increased during low dose dobutamine, without further change during high dose dobutamine. During the dobutamine infusion, there was no significant difference in ejection fraction between carvedilol and metoprolol treatment.Patients with congestive heart failure on a non-selective beta adrenoreceptor blocker or beta1 selective blocker responded differently to the inotropic drug dobutamine: the beta1 blockade caused by metoprolol could be counteracted by dobutamine, whereas with carvedilol a low dose of dobutamine increased cardiac output, and a higher dose of dobutamine caused a pressor effect. These findings may be clinically relevant when choosing an inotropic drug.
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| 7. |
- Buvall, Lisa, 1976, et al.
(författare)
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Antibodies against the beta1-adrenergic receptor induce progressive development of cardiomyopathy
- 2007
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Ingår i: J Mol Cell Cardiol. - : Elsevier BV. - 0022-2828. ; 42:5, s. 1001-7
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Tidskriftsartikel (refereegranskat)abstract
- Different immune disturbances have been found among patients with dilated cardiomyopathy (DCM), including antibodies directed against different cardiac antigens, such as the second extracellular loop of the beta(1)-adrenergic receptor. The aim of our study was to investigate antibodies directed against the second extracellular loop of the beta(1)-adrenergic receptor effect on cardiac functions at an early and late stage during DCM development. This was made in a mouse model, in which DCM was induced by immunization with the second extracellular loop of the beta(1)-adrenergic receptor. Mice were immunized for 14 or 25 weeks respectively with the second extracellular loop of the beta(1)-adrenergic receptor. At 14 weeks, there was no decreased heart function reviled by echocardiography at rest, but when dobutamine stress echocardiography was used, a lower cardiac reserve was shown in the mice with antibodies against the second extracellular loop of the beta(1)-adrenergic receptor. By 25 weeks, decreased heart function, dilatation of the left ventricle and thinner left ventricular posterior wall were observed. Further biochemical analyses at 25 weeks showed increased mRNA expressions for beta(1)-adrenergic receptor kinase, monocyte chemoattractant protein-1 and the brain natriuretic peptide as well as increased concentrations of complement factor 3 in sera in the immunized animals. Our data suggest a cardiotoxic effect of antibodies directed against the second extracellular loop of the beta(1)-adrenergic receptor and a capacity to induce DCM with progressive remodeling, decreased cardiac function, altered beta(1)AR signaling and upregulation of proinflammatory components.
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| 8. |
- Cider, Åsa, 1960, et al.
(författare)
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Immersion in warm water induces improvement in cardiac function in patients with chronic heart failure
- 2006
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Ingår i: Eur J Heart Fail. - : Wiley. - 1388-9842. ; 8:3, s. 308-13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The effects of immersion and training of patients with chronic heart failure (CHF) in warm water has not been thoroughly investigated. The aim of this study was to assess the acute hemodynamic response of immersion and peripheral muscle training in elderly patients with CHF. METHODS: Thirteen CHF patients and 13 healthy subjects underwent echocardiography on land and in a temperature-controlled swimming pool (33-34 degrees C). RESULTS: Rest. Heart rate decreased (CHF, p=0.01; control, p=0.001) and stroke volume increased (CHF, p=0.01; control, p=0.001) during water immersion in both groups, with no change in systolic or diastolic blood pressure. Ejection fraction (p<0.05) and transmitral Doppler E/A ratio (p=0.01) increased in the CHF group, with no changes in left ventricular volumes. The healthy subjects had similar responses, but also displayed an increase in cardiac output (p<0.01) and left ventricular volumes (p<0.001). Exercise. Cardiac output and systolic blood pressure increased significantly in water, in both groups. CONCLUSION: A general increase in early diastolic filling was accompanied by a decrease in heart rate, leading to an increase in stroke volume and ejection fraction in most patients with CHF during warm water immersion. These beneficial hemodynamic effects might be the reason for the previously observed good tolerability of this exercise regime.
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| 9. |
- Dalin, Martin, 1982, et al.
(författare)
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Myocardial KRASG12D expression does not cause cardiomyopathy in mice
- 2014
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 101:2, s. 229-235
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Tidskriftsartikel (refereegranskat)abstract
- AimsGerm-line mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) pathway cause developmental disorders called RASopathies. Hypertrophic cardiomyopathy (HCM) is the most common myocardial pathology and a leading cause of death in RASopathy patients. KRAS mutations are found in Noonan and cardio-facio-cutaneous syndromes. KRAS mutations, unlike mutations of RAF1 and HRAS, are rarely associated with HCM. This has been attributed to the fact that germ-line KRAS mutations cause only a moderate up-regulation of the MAPK pathway. Highly bioactive KRAS mutations have been hypothesized to cause severe cardiomyopathy incompatible with life. The aim of this study was to define the impact of KRASG12D expression in the heart.Methods and resultsTo generate mice with endogenous cardiomyocyte-specific KRASG12D expression (cKRASG12D mice), we bred mice with a Cre-inducible allele expressing KRASG12D from its endogenous promoter (Kras2LSL) to mice expressing Cre under control of the cardiomyocyte-specific α-myosin heavy chain promoter (αMHC-Cre). cKRASG12D mice showed high levels of myocardial ERK and AKT signalling. However, surprisingly, cKRASG12D mice were born in Mendelian ratios, appeared healthy, and had normal function, size, and histology of the heart.ConclusionMice with cardiomyocyte-specific KRAS G12D expression do not develop heart pathology. These results challenge the view that the level of MAPK activation correlates with the severity of HCM in RASopathies and suggests that MAPK-independent strategies may be of interest in the development of new treatments for these syndromes. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013.
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| 10. |
- Drevinge, Christina, 1983, et al.
(författare)
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Perilipin 5 is protective in the ischemic heart
- 2016
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 219, s. 446-454
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Tidskriftsartikel (refereegranskat)abstract
- Background: Myocardial ischemia is associated with alterations in cardiac metabolism, resulting in decreased fatty acid oxidation and increased lipid accumulation. Here we investigate how myocardial lipid content and dynamics affect the function of the ischemic heart, and focus on the role of the lipid droplet protein perilipin 5 (Plin5) in the pathophysiology of myocardial ischemia. Methods and results: We generated Plin5(-/-) mice and found that Plin5 deficiency dramatically reduced the triglyceride content in the heart. Under normal conditions, Plin5(-/-) mice maintained a close to normal heart function by decreasing fatty acid uptake and increasing glucose uptake, thus preserving the energy balance. However, during stress or myocardial ischemia, Plin5 deficiency resulted in myocardial reduced substrate availability, severely reduced heart function and increased mortality. Importantly, analysis of a human cohort with suspected coronary artery disease showed that a common noncoding polymorphism, rs884164, decreases the cardiac expression of PLIN5 and is associated with reduced heart function following myocardial ischemia, indicating a role for Plin5 in cardiac dysfunction. Conclusion: Our findings indicate that Plin5 deficiency alters cardiac lipid metabolism and associates with reduced survival following myocardial ischemia, suggesting that Plin5 plays a beneficial role in the heart following ischemia. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.
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| 11. |
- Grüner Sveälv, Bente, 1956, et al.
(författare)
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Benefit of warm water immersion on biventricular function in patients with chronic heart failure
- 2009
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Ingår i: Cardiovasc Ultrasound. - : Springer Science and Business Media LLC. - 1476-7120 .- 1476-7120. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Regular physical activity and exercise are well-known cardiovascular protective factors. Many elderly patients with heart failure find it difficult to exercise on land, and hydrotherapy (training in warm water) could be a more appropriate form of exercise for such patients. However, concerns have been raised about its safety.The aim of this study was to investigate, with echocardiography and Doppler, the acute effect of warm water immersion (WWI) and effect of 8 weeks of hydrotherapy on biventricular function, volumes and systemic vascular resistance. A secondary aim was to observe the effect of hydrotherapy on brain natriuretic peptide (BNP). METHODS: Eighteen patients [age 69 +/- 8 years, left ventricular ejection fraction 31 +/- 9%, peakVO2 14.6 +/- 4.5 mL/kg/min] were examined with echocardiography on land and in warm water (34 degrees C).Twelve of these patients completed 8 weeks of control period followed by 8 weeks of hydrotherapy twice weekly. RESULTS: During acute WWI, cardiac output increased from 3.1 +/- 0.8 to 4.2 +/- 0.9 L/min, LV tissue velocity time integral from 1.2 +/- 0.4 to 1.7 +/- 0.5 cm and right ventricular tissue velocity time integral from 1.6 +/- 0.6 to 2.5 +/- 0.8 cm (land vs WWI, p < 0.0001, respectively). Heart rate decreased from 73 +/- 12 to 66 +/- 11 bpm (p < 0.0001), mean arterial pressure from 92 +/- 14 to 86 +/- 16 mmHg (p < 0.01), and systemic vascular resistance from 31 +/- 7 to 22 +/- 5 resistant units (p < 0.0001).There was no change in the cardiovascular response or BNP after 8 weeks of hydrotherapy. CONCLUSION: Hydrotherapy was well tolerated by all patients. The main observed cardiac effect during acute WWI was a reduction in heart rate, which, together with a decrease in afterload, resulted in increases in systolic and diastolic biventricular function. Although 8 weeks of hydrotherapy did not improve cardiac function, our data support the concept that exercise in warm water is an acceptable regime for patients with heart failure.
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| 12. |
- Grüner Sveälv, Bente, 1956, et al.
(författare)
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Is hydrotherapy an appropriate form of exercise for elderly patients with biventricular systolic heart failure?
- 2012
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Ingår i: Journal of Geriatric Cardiology. - : Tsinghua University Press. - 1671-5411. ; 9:4, s. 408-410
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Tidskriftsartikel (refereegranskat)abstract
- Hydrotherapy (exercise in warm water) is considered to be a safe and beneficial method to use in the rehabilitation of stable heart failure patients, but there is little information on the effect of the increased venous return and enhanced preload in elderly patients with biventricular heart failure. We present a case of an elderly man who was recruited to participate in a hydrotherapy study. We compared echocardiographic data during warm water immersion with land measurements, and observed increases in stroke volume from 32 mL (land) to 42 mL (water), left ventricular ejection fraction from 22% to 24%, left ventricular systolic velocity from 4.8 cm/s to 5.0 cm/s and left atrioventricular plane displacement from 2.1 mm to 2.2 mm. By contrast, right ventricular systolic velocity decreased from 11.2 cm/s to 8.4 cm/s and right atrioventricular plane displacement from 8.1 mm to 4.7 mm. The tricuspid pressure gradient rose from 18 mmHg on land to 50 mmHg during warm water immersion. Thus, although left ventricular systolic function was relatively unaffected during warm water immersion, we observed a decrease in right ventricular function with an augmented right ventricular pressure. We recommend further investigations to observe the cardiac effect of warm water immersion on patients with biventricular systolic heart failure and at risk of elevated right ventricular pressure.
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| 13. |
- Grüner Sveälv, Bente, 1956, et al.
(författare)
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Prevalence of diastolic dysfunction in patients with ankylosing spondylitis: a cross-sectional study.
- 2015
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Ingår i: Scandinavian journal of rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 44:2, s. 111-117
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To determine the prevalence of diastolic dysfunction (DD) in patients with ankylosing spondylitis (AS) by following recommended criteria from the American Society of Echocardiography (ASE) and using single variables reflecting DD. Method: A total of 187 patients with AS (105 men; mean age 51 ± 13 years; mean duration of disease 15 ± 11 years) fulfilled the inclusion criteria and underwent pulsed-wave and tissue Doppler imaging. Results: By following ASE recommended criteria, we observed that 12% of patients with AS had mild DD. We also compared single standard Doppler values with normal age-stratified reference values and showed a wide variation in the number of patients with AS outside the 95% confidence interval (CI) of normal values depending on the variable chosen (ranging from 1.1% to 30.5%). Conclusions: By following recommended criteria, our cross-sectional study shows that DD was infrequent and mild in patients with AS.
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| 14. |
- Grüner Sveälv, Bente, 1956, et al.
(författare)
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Pronounced improvement in systolic and diastolic ventricular long axis function after treatment with metoprolol
- 2007
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Ingår i: Eur J Heart Fail. - : Wiley. - 1388-9842. ; 9:6-7, s. 678-83
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although it is well known that left ventricular (LV) function improves after treatment with beta-blockers in heart failure, little attention has been paid to the effects on LV long axis (LAX) function. AIMS: To evaluate LV LAX function after treatment with metoprolol, and to assess whether LV LAX contractile reserve could predict future long-term improvement. METHODS: Twenty-four heart failure patients were randomised to metoprolol or placebo for 6 months, followed by 6 months of open treatment with metoprolol. Rest and dobutamine stress echocardiography (DSE) was performed before and after each treatment period. RESULTS: After treatment with metoprolol, LV LAX function improved significantly, systolic velocity from 29+/-8 to 32+/-15 mm/s, p<0.01 (metoprolol) vs. 28+/-7 to 28+/-11 mm/s, ns (placebo); atrioventricular plane fractional shortening (AVP-FS) from 5.4+/-2.1 to 7.4+/-2.7%, p<0.001 (metoprolol) vs. 5.9+/-2.1 to 5.8+/-2.9%, ns (placebo). The improvement in function was maintained during DSE. LV LAX contractile reserve could not predict treatment response; the treatment effect on LV LAX function was significantly greater than the contractile reserve at baseline. The relative improvement in LV LAX function after metoprolol was 38%, compared with a 20% improvement in LV ejection fraction (EF). CONCLUSION: A significant improvement in LV LAX function was observed after treatment with metoprolol. AVP-FS and systolic velocities increased significantly, and to a greater extent than LVEF.
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| 15. |
- Haugen, Espen, 1973, et al.
(författare)
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TNFalpha antagonist upregulates interleukin-6 in rats with hypertensive heart failure.
- 2008
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Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 130:1, s. 64-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Tumor necrosis factor alpha (TNFalpha) has been shown to be a prognostic marker in heart failure, but recent clinical trials using TNFalpha antagonists in patients with severe heart failure have been disappointing. Hypertension is one of most common causes to chronic heart failure in humans. HYPOTHESIS: Suppression of a single cytokine in CHF is not an effective treatment strategy because it leads to the upregulation of other proinflammatory cytokines. OBJECTIVES: The aim of the present study was to investigate the effect of chronic treatment with a TNFalpha antagonist in a rat model of the early stage of heart failure due to hypertension. METHODS: Spontaneously hypertensive rats (SHR, n=30) and healthy Wistar Kyoto rats (WKY, n=30) were treated with either the TNFalpha antagonist etanercept or placebo for 12 weeks. At the end of the study, the rats were 26 weeks old and indices of cardiac structure, function and cytokines were analyzed. RESULTS: SHR displayed early stage of heart failure as shown by increased heart weight/body weight ratio and relative wall thickness by echocardiography, downregulated myocardial beta(1)-adrenoceptor, and upregulated myocardial brain natriuretic peptide and interleukin-6 (IL6). Chronic treatment with etanercept in SHR resulted in decreased relative wall thickness but also increased cardiac reserve and higher blood pressure. In addition, IL6 was further upregulated compared with placebo treatment. CONCLUSION: Chronic treatment with etanercept in SHR resulted in favorable cardiac remodeling, but also had a positive inotropic effect and was associated with an upregulation of IL6. These findings indicate that chronic treatment with TNFalpha antagonists is not an effective treatment strategy and may aggravate heart failure in the long term.
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| 16. |
- Isic, Azra, 1979, et al.
(författare)
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TNFalpha-antagonist neither improve cardiac remodelling or cardiac function at early stage of heart failure in diabetic rats.
- 2008
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Ingår i: Autoimmunity. - : Informa UK Limited. - 1607-842X .- 0891-6934. ; 41:6, s. 473-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Despite tumor necrosis factor alpha (TNFalpha) has been shown to be a prognostic marker in patients with heart failure and previous preclinical study with TNFalpha-antagonist has been demonstrated to improve cardiac function in acute heart failure, recent clinical trials using TNFalpha-antagonist in patients with chronic severe heart failure have been disappointing. The aim was to study why TNFalpha-antagonist may not work during long-term treatment in chronic heart failure (CHF) in experimental model. METHODS: 49 rats were used at the age of 26 weeks: healthy Whistar Kyoto rats (WKY, n = 26) and diabetic (WKY+D, n = 23). Rats in each group received either a 12-week treatment with TNFalpha-antagonist (Etanercept) or NaCl injections. RESULTS: In diabetic rats, there were increased plasma glucose level and blood pressure. By use of echocardiography diabetic rats displayed not only enlarged and thinned left ventricles but also decreased both systolic and diastolic functions. Moreover, there are increased interleukin-6 (IL6) mRNA levels. However, TNFalpha-antagonist, etanercept, does not improve either cardiac remodelling or cardiac function. IL6 mRNA level remained unchanged after treatment of etanercept. CONCLUSION: Chronic treatment of TNFalpha-antagonist has no favourable effect on either cardiac remodelling or cardiac function. It is therefore inappropriate to use TNFalpha-antagonist in CHF in diabetes as underlying cause.
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| 17. |
- Klevstig, Martina, et al.
(författare)
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Targeting acid sphingomyelinase reduces cardiac ceramide accumulation in the post-ischemic heart
- 2016
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Ingår i: Journal of Molecular and Cellular Cardiology. - : Elsevier BV. - 0022-2828 .- 1095-8584. ; 93, s. 69-72
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Tidskriftsartikel (refereegranskat)abstract
- Ceramide accumulation is known to accompany acute myocardial ischemia, but its role in the pathogenesis of ischemic heart disease is unclear. In this study, we aimed to determine how ceramides accumulate in the ischemic heart and to determine if cardiac function following ischemia can be improved by reducing ceramide accumulation. To investigate the association between ceramide accumulation and heart function, we analyzed myocardial left ventricle biopsies from subjects with chronic ischemia and found that ceramide levels were higher in biopsies from subjects with reduced heart function. Ceramides are produced by either de novo synthesis or hydrolysis of sphingomyelin catalyzed by acid and/or neutral sphingomyelinase. We used cultured HL-1 cardiomyocytes to investigate these pathways and showed that acid sphingomyelinase activity rather than neutral sphingomyelinase activity or de novo sphingolipid synthesis was important for hypoxia-induced ceramide accumulation. We also used mice with a partial deficiency in acid sphingomyelinase (Smpd1(+/-) mice) to investigate if limiting ceramide accumulation under ischemic conditions would have a beneficial effect on heart function and survival. Although we showed that cardiac ceramide accumulation was reduced in Smpd1(+/-) mice 24 h after an induced myocardial infarction, this reduction was not accompanied by an improvement in heart function or survival. Our findings show that accumulation of cardiac ceramides in the post-ischemic heart is mediated by acid sphingomyelinase. However, targeting ceramide accumulation in the ischemic heart may not be a beneficial treatment strategy.
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| 18. |
- Klingberg, Eva, et al.
(författare)
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Aortic Regurgitation Is Common in Ankylosing Spondylitis : Time for Routine Echocardiography Evaluation?
- 2015
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Ingår i: American Journal of Medicine. - : Elsevier. - 0002-9343 .- 1555-7162. ; 128:11, s. 1244-50
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The aim of this study was to assess the prevalence of aortic regurgitation and any relation to disease activity and specific human leukocyte antigen (HLA)-B27 subtypes in patients with ankylosing spondylitis.METHODS: Transthoracic echocardiography was performed in 187 patients (105 men), mean age (SD) 50 (13) years, and mean disease duration 24 (13) years, and was related to demographic, clinical, radiographic, electrocardiographic, and laboratory data.RESULTS: Aortic regurgitation was found in 34 patients (18%; 95% confidence interval [CI], 12%-24%): mild in 24, moderate in 9, and severe in one. The prevalence was significantly higher than expected from population data. Conduction system abnormalities were documented in 25 patients (13%; 95% CI, 8%-18%), and significantly more likely in the presence of aortic regurgitation (P = .005), which was related to increasing age and longstanding disease, and increased from ∼20% in the 50s to 55% in the 70s. It was also independently associated with disease duration, with higher modified Stoke Ankylosing Spondylitis Spine Score, and with a history of anterior uveitis. HLA-B27 was present in similar proportions in the presence vs absence of aortic regurgitation. For comparison, clinically significant coronary artery disease was present in 9 patients (5%; 95% CI, 2%-8%).CONCLUSION: Patients with ankylosing spondylitis frequently have cardiac abnormalities, but they more often consist of disease-related aortic regurgitation or conduction system abnormalities than manifestations of atherosclerotic heart disease. Because aortic regurgitation or conduction abnormalities might cause insidious symptoms not easily interpreted as of cardiac origin, we suggest that both electrocardiography and echocardiography evaluation should be part of the routine management of patients with ankylosing spondylitis.
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| 19. |
- Li, Xiujuan, et al.
(författare)
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Suppressed Vascular Leakage and Myocardial Edema Improve Outcome From Myocardial Infarction
- 2020
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The acute phase of myocardial infarction (MI) is accompanied by edema contributing to tissue damage and disease outcome. Here, we aimed to identify the mechanism whereby vascular endothelial growth factor (VEGF)-A induces myocardial edema in the acute phase of MI to eventually promote development of therapeutics to specifically suppress VEGFA-regulated vascular permeability while preserving collateral vessel formation.Methods and Results: VEGFA regulates vascular permeability and edema by activation of VEGF receptor-2 (VEGFR2), leading to induction of several signaling pathways including the cytoplasmic tyrosine kinase c-Src. The activated c-Src in turn phosphorylates vascular endothelial (VE)-cadherin, leading to dissociation of endothelial adherens junctions. A particular tyrosine at position 949 in mouse VEGFR2 has been shown to be required for activation of c-Src. Wild-type mice and mice with phenylalanine replacing tyrosine (Y) 949 in VEGFR2 (Vegfr2Y949F/Y949F) were challenged with MI through permanent ligation of the left anterior descending coronary artery. The infarct size was similar in wild-type and mutant mice, but left ventricular wall edema and fibrinogen deposition, indicative of vascular leakage, were reduced in the Vegfr2Y949F/Y949F strain. When challenged with large infarcts, the Vegfr2Y949F/Y949F mice survived significantly better than the wild-type strain. Moreover, neutrophil infiltration and levels of myeloperoxidase were low in the infarcted Vegfr2Y949F/Y949F hearts, correlating with improved survival. In vivo tyrosine phosphorylation of VE-cadherin at Y685, implicated in regulation of vascular permeability, was induced by circulating VEGFA in the wild-type but remained at baseline levels in the Vegfr2Y949F/Y949F hearts.Conclusion: Suppression of VEGFA/VEGFR2-regulated vascular permeability leads to diminished edema without affecting vascular density correlating with improved myocardial parameters and survival after MI.
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| 20. |
- Mardani, Ismena, et al.
(författare)
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Plin2-deficiency reduces lipophagy and results in increased lipid accumulation in the heart.
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Myocardial dysfunction is commonly associated with accumulation of cardiac lipid droplets (LDs). Perilipin 2 (Plin2) is a LD protein that is involved in LD formation, stability and trafficking events within the cell. Even though Plin2 is highly expressed in the heart, little is known about its role in myocardial lipid storage. A recent report shows that cardiac overexpression of Plin2 result in massive myocardial steatosis suggesting that Plin2 stabilizes LDs. In this study, we hypothesized that deficiency in Plin2 would result in reduced myocardial lipid storage. In contrast to our hypothesis, we found increased accumulation of triglycerides in hearts, and specifically in cardiomyocytes, from Plin2-/- mice. Although Plin2-/- mice had markedly enhanced lipid levels in the heart, they had normal heart function under baseline conditions and under mild stress. However, after an induced myocardial infarction, stroke volume and cardiac output were reduced in Plin2-/- mice compared with Plin2+/+ mice. We further demonstrated that the increased triglyceride accumulation in Plin2-deficient hearts was caused by altered lipophagy. Together, our data show that Plin2 is important for proper hydrolysis of LDs.
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| 21. |
- Mobini, Reza, 1965, et al.
(författare)
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Influence of central inhibition of sympathetic nervous activity on myocardial metabolism in chronic heart failure: acute effects of the imidazoline I1-receptor agonist moxonidine.
- 2006
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Ingår i: Clinical science (London, England : 1979). - 0143-5221. ; 110:3, s. 329-36
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Tidskriftsartikel (refereegranskat)abstract
- Although beta-adrenergic blockade is beneficial in heart failure, inhibition of central sympathetic outflow using moxonidine has been associated with increased mortality. In the present study, we studied the acute effects of the imidazoline-receptor agonist moxonidine on haemodynamics, NA (noradrenaline) kinetics and myocardial metabolism. Fifteen patients with CHF (chronic heart failure) were randomized to a single dose of 0.6 mg of sustained-release moxonidine or matching placebo. Haemodynamics, NA kinetics and myocardial metabolism were studied over a 2.5 h time period. There was a significant reduction in pulmonary and systemic arterial pressures, together with a decrease in cardiac index in the moxonidine group. Furthermore, there was a simultaneous reduction in systemic and cardiac net spillover of NA in the moxonidine group. Analysis of myocardial consumption of substrates in the moxonidine group showed a significant increase in non-esterified fatty acid consumption and a possible trend towards an increase in myocardial oxygen consumption compared with the placebo group (P=0.16). We conclude that a single dose of moxonidine (0.6 mg) in patients already treated with a beta-blocker reduced cardiac and overall sympathetic activity. The finding of increased lipid consumption without decreased myocardial oxygen consumption indicates a lack of positive effects on myocardial metabolism under these conditions. We suggest this might be a reason for the failure of moxonidine to prevent deaths in long-term studies in CHF.
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| 22. |
- Redfors, Björn, et al.
(författare)
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Effects of doxorubicin on myocardial expression of apolipoprotein-B.
- 2012
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Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1651-2006 .- 1401-7431. ; 46:2
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Doxorubicin (DOX) is an effective antitumor agent against a variety of human malignancies but is associated with deleterious side effects, including myocardial damage and heart failure. Myocardial apoB-containing lipoprotein (apoB) is upregulated post myocardial infarction and has been shown to be cardioprotective in this setting by unloading excessive lipid. The aim of this study was to investigate whether apoB expression is increased also in DOX-induced heart failure and whether apoB overexpression protects the heart in DOX-induced myocardial injury. Design: Cardiac function and energy metabolism was studied in mice and rats 24 hours after intraperitoneally administered DOX. Results: We found that the content of apoB was decreased in rat myocardium 24 hours after DOX injection. In contrast, apoB content was increased in the infarcted myocardium of rats 24 hours post ischemia-reperfusion. Moreover, transgenic mice overexpressing apoB had better cardiac function and lower intracellular lipid accumulation compared to wild type mice 24h post DOX. Conclusions: Our findings indicate that depression of the myocardial apoB system may contribute to DOX-induced cardiac injury and that overexpression of apoB is protective, not only in ischemically damaged myocardium, but also in DOX-induced heart failure.
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| 23. |
- Redfors, Björn, et al.
(författare)
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Effects of doxorubicin on myocardial expression of apolipoprotein-B.
- 2012
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Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1401-7431 .- 1651-2006. ; 46:2, s. 93-98
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Tidskriftsartikel (refereegranskat)abstract
- Abstract OBJECTIVE: Doxorubicin (DOX) is an effective antitumour agent against a variety of human malignancies but is associated with deleterious side effects, including myocardial damage and heart failure. Myocardial apoB-containing lipoprotein (apoB) is upregulated post myocardial infarction and has been shown to be cardioprotective in this setting by unloading excessive lipid. The aim of this study was to investigate whether apoB expression is increased also in DOX-induced heart failure and whether apoB overexpression protects the heart in DOX-induced myocardial injury. DESIGN: Cardiac function and energy metabolism was studied in mice and rats 24 hours after intraperitoneally administered DOX. RESULTS: We found that the content of apoB was decreased in rat myocardium 24 hours after DOX injection. In contrast, apoB content was increased in the infarcted myocardium of rats 24 hours post ischemia-reperfusion. Moreover, transgenic mice overexpressing apoB had better cardiac function and lower intracellular lipid accumulation compared to wild type mice 24 hours post DOX.
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| 24. |
- Råmunddal, Truls, 1973, et al.
(författare)
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Overexpression of apolipoprotein B attenuates pathologic cardiac remodeling and hypertrophy in response to catecholamines and after myocardial infarction in mice.
- 2012
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 72:3, s. 230-236
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Introduction. The heart produces apolipoprotein (apo) B-containing lipoproteins which enables cardiac export of potentially cardiotoxic lipids. We hypothesized that overexpression of apoB attenuates the pathologic cardiac remodeling and hypertrophic response following pathological stimuli such as chronic adrenergic overstimulation and myocardial infarction (MI). Methods. Cardiac hypertrophy was induced by a chronic infusion of isoproterenol (ISO) 15 mg/kg/day for 3 weeks in human apoB transgenic mice (n9) and in non-transgenic wild-type mice (n10). As controls, apoB transgenic (N10) and wild-type mice (N10) saline infusions were used. Transthoracic echocardiography was performed at baseline and after 3 weeks of treatment to evaluate left ventricular (LV) function and morphology. To investigate the effects of expression on postinfarct hypertrophic response we induced MI in apoB transgenic mice (n8) and in wild-type controls (n11). The hearts were explanted and weighed 6 weeks post MI. Results. At baseline, WT mice had higher BW and LV mass (LVM) compared to the apoB mice. The increase in LV mass and dimensions after 3 weeks of treatment with ISO was significantly lower while systolic function was signifi cantly better in the apoB group. Six weeks post MI the apoB mice had significantly lower heart weight and heart weight to body weight ratio. The infarct size was similar in both groups. Conclusion. Overexpression of apoB attenuates the pathologic remodeling and hypertrophic response to chronic adrenergic stimulation and MI. Our results indicate that cardiac expression of apoB-containing lipoproteins might be an important regulator of myocardial structure and function.
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| 25. |
- Råmunddal, Truls, 1973, et al.
(författare)
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Overexpression of apolipoprotein-B improves cardiac function and increases survival in mice with myocardial infarction.
- 2009
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Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 385:3, s. 336-40
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The heart produces apolipoprotein-B containing lipoproteins (apoB) whose function is not well understood. The aim of this study was to evaluate importance of myocardial apoB for cardiac function, structure and survival in myocardial infarction (MI) and heart failure (HF). METHODS AND RESULTS: MI was induced in mice (n=137) and myocardial apoB content was measured at 30 min, 3, 6, 24, 48, 120 h and 8 weeks post-MI. Transgenic mice overexpressing apoB (n=27) and genetically matched controls (n=27) were used to study the effects of myocardial apoB on cardiac function, remodeling, arrhythmias and survival after MI. Echocardiography was performed at rest and stress conditions at baseline, 2, 4 and 6 week post-MI and cumulative survival rate was registered. The myocardial apoB content increased both in the injured and the remote myocardium (p<0.05) in response to ischemic injury. ApoB mice had 2-fold higher survival rate (p<0.05) and better systolic function (p<0.05) post-MI. CONCLUSION: Overexpression of apoB in the heart increases survival and improves cardiac function after acute MI. Myocardial apoB may be an important cardioprotective system in settings such as myocardial ischemia and HF.
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| 26. |
- Scharin Täng, Margareta, 1962, et al.
(författare)
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Cardiac reserve in the transplanted heart: effect of a graft polymorphism in the beta1-adrenoceptor
- 2007
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Ingår i: The Journal of Heart and Lung Transplantation. - : Elsevier BV. - 1053-2498. ; 26:9, s. 915-20
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Polymorphism of the beta1-adrenoceptor (beta1-AR) affects outcome and beta-blocker efficacy in patients with heart failure. We studied the influence of the beta1-AR Ser49Gly polymorphism on cardiac reserve in transplanted hearts. METHODS: Beta1-AR polymorphism was determined by allelic discrimination analysis. Patients were divided into two groups: either homozygous for Ser49 (n = 15) or with Gly49 in one or both alleles (Gly49; n = 5). Patients underwent a maximal bicycle exercise test and echocardiographic evaluation at rest and during low-dose dobutamine stress. RESULTS: Patients with Gly49 grafts had better physical endurance (144 +/- 26 vs 112 +/- 31 W, p = 0.03), a trend toward better chronotropic reserve (deltaHR 64 +/- 13 vs 47 +/- 16 bpm, p = 0.056) during exercise, and lower resting heart rate (82 +/- 7 vs 90 +/- 7 bpm, p = 0.04) than those homozygous for Ser49. There were no significant differences in left ventricular ejection fraction (LVEF), with the exception of a decrease in cardiac reserve in patients with the Gly49 variants at the lowest dose of dobutamine (deltaLVEF -4.4 +/- 1.5 vs 2.2 +/- 5.8%, p = 0.04). Doppler myocardial tissue velocities of early relaxation were increased in patients with the Gly49 variants compared with patients homozygous for Ser49, both at rest (14.5 +/- 3.2 vs 10.4 +/- 2.0 cm/s, p = 0.03) and during the lowest dose of dobutamine (15.0 +/- 3.7 vs 10.9 +/- 2.5 cm/s, p = 0.04). CONCLUSIONS: Heart transplant patients with the beta1-AR Gly49 variants had a lower heart rate, and better stress endurance and diastolic function compared with patients homozygous for Ser49. They also showed a trend toward better chronotropic reserve. These results provide a possible explanation for differences in cardiac reserve among patients with heart transplants.
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| 27. |
- Scharin Täng, Margareta, 1962
(författare)
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Importance of cardiac reserve for evaluation and prediction of cardiac function and morbidity assessed by low-dose dobutamine stress echocardiography
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis aimed to evaluate the cardiac reserves capacity to be used to predict treatment effects, sub clinical heart disease and to evaluate b1-adrenoceptor (AR) gene polymorphism (Ser49Gly). Studies were performed in patients with dilated cardiomyopathy, in rats (young, healthy, diabetic and hypertensive), in mice (immunized against the ?1AR) and in heart-transplanted patients. The cardiac reserve was assessed by low-dose dobutamine stress echocardiography. In both patient studies by dobutamine infusion until an increased baseline heart rate with ~20 bpm, in rats at doses of 10 µg/kg/min and 20 µg/kg/min dobutamine and in mice after an intraperitoneally injection of 1 µg dobutamine/g of body weight. Both global and regional cardiac reserve can be used to predict treatment effect of metoprolol in dilated cardiomyopathy patients. However, only cardiac reserve in the basal segments of the heart was independently associated with recovery. In heart transplanted patients a gene-polymorphism in the ?1AR in the graft affects cardiac reserve. Patients having the ?1AR Gly49 variants had a lower resting heart rate, a better stress endurance and chronotropic reserve than patients homozygous for Ser49. They also had better diastolic function shown as better lusitropic capacity. Cardiac reserve can also be used to investigate sub clinical heart disease in ?1AR immunized mice and to predict heart disease development in these animals. Furthermore, cardiac reserve decreases with age and is depressed both in hypertension and in diabetes rat model. We conclude that cardiac reserve can predict left ventricular recovery during beta-blocker treatment and that ?1AR polymorphism affects cardiac reserve in humans. Cardiac reserve decreases with age and is impaired both in severe heart disease and during progression of myocardial dysfunction in rats. Furthermore, cardiac reserve can be used to predict cardiomyopathy development after ?1AR immunization in mice.
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| 28. |
- Scharin Täng, Margareta, 1962, et al.
(författare)
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Importance of circulating IGF-1 for normal cardiac morphology, function and post infarction remodeling
- 2012
-
Ingår i: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - : Elsevier BV. - 1096-6374. ; 22:6, s. 206-211
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Tidskriftsartikel (refereegranskat)abstract
- IGF-1 plays an important role in cardiovascular homeostasis, and plasma levels of IGF-1 correlate inversely with systolic function in heart failure. It is not known to what extent circulating IGF-1 secreted by the liver and local autocrine/paracrine IGF-1 expressed in the myocardium contribute to these beneficial effects on cardiac function and morphology. In the present study, we used a mouse model of liver-specific inducible deletion of the IGF-1 gene (LI-IGF-1 -/- mouse) in an attempt to evaluate the importance of circulating IGF-I on cardiac morphology and function under normal and pathological conditions, with an emphasis on its regulatory role in myocardial phosphocreatine metabolism. Echocardiography was performed in LI-IGF-1 -/- and control mice at rest and during dobutamine stress, both at baseline and post myocardial infarction (MI). High-energy phosphate metabolites were compared between LI-IGF-1 -/- and control mice at 4weeks post MI. We found that LI-IGF-1 -/- mice had significantly greater left ventricular dimensions at baseline and showed a greater relative increase in cardiac dimensions, as well as deterioration of cardiac function, post MI. Myocardial creatine content was 17.9% lower in LI-IGF-1 -/- mice, whereas there was no detectable difference in high-energy nucleotides. These findings indicate an important role of circulating IGF-1 in preserving cardiac structure and function both in physiological settings and post MI.
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| 29. |
- Scharin Täng, Margareta, 1962, et al.
(författare)
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Influence of age, hypertension, and diabetes on cardiac reserve in a rat model
- 2007
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Ingår i: J Am Soc Echocardiogr. - : Elsevier BV. - 0894-7317. ; 20:6, s. 731-7
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Tidskriftsartikel (refereegranskat)abstract
- Background Assessment of cardiac reserve is used to disclose heart disease and to predict outcome in humans. Low-dose dobutamine stress echocardiography (DSE) was used to study the influence of age, hypertension, and diabetes on cardiac reserve in the rat model. Methods Low-dose DSE was performed in four groups: 10 young, 10 adult, and 10 diabetic Whistar Kyoto rats, and 10 spontaneously hypertensive rats. Results Cardiac reserve assessed by low-dose DSE was shown to decrease with age and was impaired both in rat models of hypertension and diabetes. Less information was provided by measuring cardiac function at rest. Conclusions Cardiac reserve in rats is similar to humans in that it decreases with age and is impaired both in severe heart disease and during progression of myocardial dysfunction. We have shown that low-dose DSE in rats is a feasible and reliable method that could be used to study the development of heart disease.
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| 30. |
- Scharin Täng, Margareta, 1962, et al.
(författare)
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Native cardiac reserve predicts survival in acute post infarction heart failure in mice.
- 2007
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Ingår i: Cardiovascular Ultrasound. - : Springer Science and Business Media LLC. - 1476-7120. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: Cardiac reserve can be used to predict survival and outcome in patients with heart failure. The aim of this study was to investigate if native cardiac reserve could predict survival after myocardial infarction (MI) in mice. METHOD: We investigated 27 healthy C57Bl6 mice (male, 10-12 weeks old) with echocardiography using a high-frequency 15-MHz linear transducer. Investigations were performed both at rest and after pharmacological stress induced by dobutamine (1 ug/g body weight i.p.). The day after the echocardiography examination, a large MI was induced by ligation of the left anterior descending (LAD) coronary artery for evaluation of mortality rate. Result: Two weeks after induction of MI, 7 mice were alive (26%). Evaluation of the difference between the surviving and deceased animals showed that the survivors had a better native ability to increase systolic performance (DeltaLVESd -1.86 vs -1.28mm p=0.02) upon dobutamine challenge, resulting in a better cardiac reserve (DeltaFS 37 vs 25% p=0.02 and DeltaCO 0.27 vs -0.10 ml/min p=0.02) and a better chronotropic reserve (DeltaR-R interval -68 vs -19 ms p< 0.01). A positive relationship was found between ability to survive and both cardiac (p<0.05) and chronotropic reserve (p<0.05) when the mice were divided into three groups: survivors, surviving <7 days, and surviving <1 day. CONCLUSION: We conclude that before MI induction the surviving animals had a better cardiac function compared with the deceased. This indicates that native cardiac and chronotropic reserve may be an important determinant and predictor of survival in the setting of large MI and post-infarction heart failure.
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| 31. |
- Scharin Täng, Margareta, 1962, et al.
(författare)
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The function of left ventricular basal segments is most important for long-term recovery
- 2007
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Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 121:3, s. 284-90
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Tidskriftsartikel (refereegranskat)abstract
- Adrenergic beta-blockade is the most potent pharmacological therapy for the improvement of global left ventricular (LV) function in heart failure. A substantial portion of patients responds poorly to beta-blockers, but there is scarce information about LV regional function and recovery. We intended to evaluate the effects of beta-blockade on LV regional function and recovery, contractile reserve (CR) and response to long-term treatment.Twenty-two patients with heart failure were investigated at rest and during dobutamine stress echocardiography (DSE), before and after 6 months of metoprolol treatment. LV function was evaluated by global ejection fraction (EF), and by regional function in basal, mid and apical segments.Recovery of LV global function (increase in EF >5%) after metoprolol treatment was significantly and best correlated to CR in basal segments of the ventricle (r=0.79, p<0.001), in comparison with function of mid and apical segments. The correlation between global recovery and global CR was r=0.55, p=0.007. In a multivariate logistic regression, including global and regional CR, age, gender, etiology of heart failure, ACE-inhibitor treatment, heart rate, and baseline EF, only basal CR was independently associated with recovery, OR 1.07 [95% CI, 1.01-1.21], p=0.019.The strongest association for prediction of LV recovery after metoprolol treatment was found regarding function of basal segments of the ventricle. Patients that responded favourably to beta-blockade had a significantly better CR, and treatment effect, in these segments. This gives further evidence for the importance of myocardial function in basal segments to the contribution of recovery and LV global function.
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| 32. |
- Scharin Täng, Margareta, 1962, et al.
(författare)
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Velocity Vector Imaging Fails to Quantify Regional Myocardial Dysfunction in a Mouse Model of Isoprenaline-Induced Cardiotoxicity
- 2012
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Ingår i: Echocardiography-a Journal of Cardiovascular Ultrasound and Allied Techniques. - : Wiley. - 0742-2822. ; 29:7, s. 818-826
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Tidskriftsartikel (refereegranskat)abstract
- Background: Regional myocardial deformation patterns are important in a variety of cardiac diseases, including stress-induced cardiomyopathy. Velocity-vector-based imaging is a speckle-tracking echocardiography (STE)-based algorithm that has been shown to allow in-depth cardiac phenotyping in humans. Regional posterior wall myocardial dysfunction occurs during severe isoprenaline stress in mice. We have previously shown that regional posterior wall end-systolic transmural strain decreases after severe isoprenaline toxicity in mice. We hypothesize that STE can detect and further quantify these perturbations. Methods and results: Twenty-three mice underwent echocardiographic examination using the VEVO2100 system. Regional transmural radial strain and strain rate were calculated in both parasternal short-axis and parasternal long-axis cine loops using the VisualSonics VEVO 2100 velocity vector imaging (VVI) STE algorithm. Eight C57BL/6 mice underwent baseline echocardiographic examination using the VisualSonics VEVO 770 system, which can acquire >1,000 frames/s cine loops. In a parasternal short-axis cine loop, the heart was divided into six segments, and regional fractional wall thickening (FWT) was assessed manually. The same protocols were also performed 90 minutes post 400 mg/kg intraperitoneally isoprenaline. Regional myocardial FWT is uniform at baseline but increases significantly in anterolateral segments, whereas it decreases significantly in posterior segments (P < 0.05). A similar pattern is seen using the VVI algorithm although the variance is larger, and differences are smaller and fail to reach significance. Conclusions: VVI is less sensitive in detecting regional perturbations in myocardial function than manual tracing, possibly due to the low frame rate in the cine loops used.
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| 33. |
- Shao, Yangzhen, 1981, et al.
(författare)
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A mouse model reveals an important role for catecholamine-induced lipotoxicity in the pathogenesis of stress-induced cardiomyopathy.
- 2013
-
Ingår i: European journal of heart failure. - : Wiley. - 1879-0844 .- 1388-9842. ; 15:1, s. 9-22
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Tidskriftsartikel (refereegranskat)abstract
- AimStress-induced cardiomyopathy (SIC), also known as takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular dysfunction (akinesia) involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC, but the pathomechanisms involved are unknown. We tested the hypothesis that excessive catecholamines cause perturbation of myocardial lipid metabolism and that cardiac lipotoxicity is responsible for the pathogenesis of SIC. METHODS AND RESULTS: A single dose injection of isoprenaline (ISO; 400 mg/kg) induced SIC-like regional akinesia in mice. Oil red O staining revealed severe lipid accumulation in the heart 2 h post-ISO. Both intramyocardial lipid accumulation and cardiac function were normalized within 1 week post-ISO and no significant amount of fibrosis was detected. We found that gene expression of lipid importers and exporters (ApoB lipoprotein) was depressed 2 h post-ISO. These results were confirmed by similar findings in SIC patients and in ISO/patient serum-stressed HL-1 cardiomyocytes. Moreover, overexpression of ApoB in the heart was found to protect against the development of ISO-induced cardiac toxicity and cardiac dysfunction. We also found that ISO-induced intramyocardial lipid accumulation caused electrophysiological disturbance and stunning in ISO/patient serum-stressed HL-1 cardiomyocytes. CONCLUSIONS: The present study demonstrates that lipotoxicity is closely associated with catecholamine-induced myocardial dysfunction, including neurogenic stunning, metabolic stunning, and electrophysiological stunning. Cardiac lipotoxicity may originate from direct inhibition of myocardial ApoB lipoprotein and subsequent decreased lipid export, caused by supraphysiological levels of catecholamines.
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| 34. |
- Shao, Yangzhen, 1981, et al.
(författare)
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Adenosine prevents isoprenaline-induced cardiac contractile and electrophysiological dysfunction.
- 2013
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Ingår i: European journal of pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 718:1-3, s. 475-483
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Tidskriftsartikel (refereegranskat)abstract
- Excessive levels of catecholamines are believed to contribute to cardiac dysfunction in a variety of disease states, including myocardial infarction and heart failure, and are particularly implicated in stress-induced cardiomyopathy, an increasingly recognized cardiomyopathy associated with significant morbidity and mortality. We have previously shown that a high dose of isoprenaline induces reversible regional dysfunction of the left ventricle in mice. We now hypothesize that adenosine can prevent cardiac dysfunction in this mouse model of stress-induced cardiomyopathy. Hundred male C57BL/6 mice were injected with 400mg/kg isoprenaline and then randomized to either 400mg/kg adenosine or saline. Cardiac function was evaluated by echocardiography at baseline and 2, 24, 48, 72, 96 and 120min post isoprenaline. Myocardial fibrosis was quantified after 10 days. Intracellular lipid accumulation was quantified after 2 and 24h. Electrophysiological parameters and degree of lipid accumulation were evaluated in cultured HL1 cardiomyocytes. Two hours post isoprenaline treatment, echocardiographic parameters of global and posterior wall regional function were significantly better in adenosine-treated mice (P<0.05). This difference persisted at 24h, but saline-treated mice gradually recovered over the next 96h. Intracellular lipid accumulation was also significantly lower in adenosine mice. We found no sign of fibrosis in the adenosine mice, whereas the extent of fibrosis in isoprenaline mice was 1.3% (P<0.05). Furthermore, adenosine-treated HL1 cells showed preserved electrophysiological function and displayed less severe intracellular lipid accumulation in response to isoprenaline. In conclusion, adenosine attenuates isoprenaline-induced cardiac dysfunction in mice and cells.
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| 35. |
- Shao, Yangzhen, 1981, et al.
(författare)
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Novel rat model reveals important roles of β-adrenoreceptors in stress-induced cardiomyopathy.
- 2013
-
Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 168:3, s. 1943-1950
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Stress-induced cardiomyopathy (SIC), also known as Takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular akinesia involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC but the pathophysiological pathways and receptors involved are unknown. METHODS: Sprague Dawley rats (~300g) were injected with a single dose of the β-adrenergic agonist isoprenaline (ISO, i.p.) and echocardiography was used to study cardiac function. The akinetic part of the left ventricle was biopsied in six SIC patients. Amount of intracellular lipid and glycogen as well as degree of permanent cardiac damage were assessed by histology. RESULTS: In rats, ISO at doses ≥50mg/kg induced severe SIC-like regional akinesia that completely resolved within seven days. Intracellular lipid content was higher in akinetic, but not in normokinetic myocardium in both SIC patients and rats. β2-receptor blockade or Gi-pathway inhibition was associated with less widespread akinesia and low lipid accumulation but significantly increased acute mortality. CONCLUSIONS: We provide a novel rat model of SIC that supports the hypothesis of circulating catecholamines as initiators of SIC. We propose that the β-adrenoreceptor pathway is important in the setting of severe catecholamine overstimulation and that perturbations of cardiac metabolism occur in SIC.
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| 36. |
- Shao, Yangzhen, 1981, et al.
(författare)
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Novel Simple Approach for Detection of Regional Perturbations of Cardiac Function in Mouse Models of Cardiovascular Disease
- 2013
-
Ingår i: Echocardiography. - : Wiley. - 1540-8175 .- 0742-2822. ; 30:7, s. 843-849
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Transthoracic murine echocardiography is a cornerstone of small animal research, but conventional methods cannot detect regional perturbations in cardiac function. Reliable assessment of regional cardiac function would be of value in transgenic models of myocardial disease. Until now automatized algorithms for achieving this suffers from a number of drawbacks. We developed a simple algorithm for rapidly assessing the relative myocardial radial thickening that occurs between end-diastole and end-systole, that is, regional radial transmural end-systolic strain (RTESS). METHODS AND RESULTS: Echocardiographic assessment was performed in mice at baseline (n = 8), 2 hours postintraperitoneal isoprenaline (ISO) injection (n = 8), and 10 days postmyocardial infarction (post-MI) (n = 6). A >1000 frames/sec cine loop was acquired by the ECG-gated Kilohertz visualization technique in the parasternal short-axis projection at 3 mm below the mitral annulus. Endo- and epicardial borders were traced at end-diastole and end-systole and RTESS was calculated for each of n segments by the algorithm. The intra- and inter-observer coefficients of variation for segmental RTESS assessment were 5.11 and 7.32, respectively. At baseline, average segmental RTESS was 56.75% and RTESS was similar in all cardiac segments regardless of how many segments the heart was divided into. In the akinetic myocardium of MI and ISO mice, 47.36% and 26.22% length of the endocardium, respectively, RTESS was near zero and significantly different from the remaining myocardium. CONCLUSION: We describe a simple and straightforward approach to quantify regional myocardial deformation in mouse models of cardiovascular disease.
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