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Fraccarollo D.,Klinik fuer Kardiologie und Angiologie | Galuppo P.,Klinik fuer Kardiologie und Angiologie | Motschenbacher S.,Universitatsklinikum Wuerzburg | Ruetten H.,Sanofi S.A. | And 2 more authors.
Basic Research in Cardiology | Year: 2014

Impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signaling is involved in the pathogenesis of ischemic heart diseases, yet the impact of long-term sGC activation on progressive cardiac remodeling and heart failure after myocardial infarction (MI) has not been explored. Moreover, it is unknown whether stimulating the NO/heme-independent sGC provides additional benefits to ACE inhibition in chronic ischemic heart failure. Starting 10 days after MI, rats were treated with placebo, the sGC activator ataciguat (10 mg/kg/twice daily), ramipril (1 mg/kg/day), or a combination of both for 9 weeks. Long-term ataciguat therapy reduced left ventricular (LV) diastolic filling pressure and pulmonary edema, improved the rightward shift of the pressure-volume curve, LV contractile function and diastolic stiffness, without lowering blood pressure. NO/heme-independent sGC activation provided protection over ACE inhibition against mitochondrial superoxide production and progressive fibrotic remodeling, ultimately leading to a further improvement of cardiac performance, hypertrophic growth and heart failure. We found that ataciguat stimulating sGC activity was potentiated in (myo)fibroblasts during hypoxia-induced oxidative stress and that NO/heme-independent sGC activation modulated fibroblast-cardiomyocyte crosstalk in the context of heart failure and hypoxia. In addition, ataciguat inhibited human cardiac fibroblast differentiation and extracellular matrix protein production in response to TGF-β1. Overall, long-term sGC activation targeting extracellular matrix homeostasis conferred cardioprotection against progressive cardiac dysfunction, pathological remodeling and heart failure after myocardial infarction. NO/heme-independent sGC activation may prove to be a useful therapeutic target in patients with chronic heart failure and ongoing fibrotic remodeling. © 2014 Springer-Verlag.


Fraccarollo D.,Klinik fuer Kardiologie und Angiologie | Fraccarollo D.,Universitatsklinikum | Berger S.,German Cancer Research Center | Galuppo P.,Klinik fuer Kardiologie und Angiologie | And 7 more authors.
Circulation | Year: 2011

Background- Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MR) that were generated with a conditional MR allele (MR) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter. Methods and Results- Control (MR, MR) and MR mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MR mice. Chronically infarcted MR mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O2 production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MR mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor-κB and reduced apoptosis early after myocardial infarction. Conclusion- Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression. Copyright © 2011 American Heart Association. All rights reserved.


Galuppo P.,Klinik fuer Kardiologie und Angiologie | Bauersachs J.,Klinik fuer Kardiologie und Angiologie
European Journal of Clinical Investigation | Year: 2012

The classical view of aldosterone actions via the mineralocorticoid receptor (MR) limited to control of fluid balance and blood pressure homoeostasis has been progressively overcome by clinical and experimental evidence emphasizing the pleiotropic role of MR activation in the pathogenesis of cardiovascular disease. Clinical studies have shown the benefit of MR blockade in patients with left ventricular dysfunction and heart failure after myocardial infarction (MI), hypertension or diabetic nephropathy. Deleterious effects of MR activation include cardiac structural and electrical remodelling, cardiovascular fibrosis, inflammation and oxidative stress. Complexity of pathophysiological role of MR derives from the presence of circulating glucocorticoids at higher concentrations than aldosterone and the equal affinity of the MR for aldosterone, cortisol and corticosterone. Recent experimental studies using different animal models and genetic tools have deeply explored the cell-specific functional role of MR in cardiovascular pathology. This review addresses emerging preclinical studies as well as ongoing clinical trials regarding MR activation in MI and failure. © 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.


Fraccarollo D.,Klinik fuer Kardiologie und Angiologie | Bauersachs J.,Klinik fuer Kardiologie und Angiologie
Trends in Cardiovascular Medicine | Year: 2011

Clinical trials have clearly demonstrated that mineralocorticoid receptor (MR) blockade improves outcome in patients with chronic systolic heart failure and left ventricular dysfunction after myocardial infarction; however, the underlying mechanisms as well as the cell-specific functional role of MR activation are still under investigation. Extrarenal effects of MR blockade on cardiovascular extracellular matrix turnover and oxidative stress, on myocardial structural and electrical remodeling, and on sympathoadrenergic stimulation, platelet activation, endothelial dysfunction, and macrophage polarization appear to be important mechanisms. Recent scientific advances, involving mice with cardiomyocyte-restricted inactivation of the MR gene suggest that the clinical benefits of MR blocking therapy in myocardial infarction and heart failure are mediated largely via cardiomyocyte-dependent mechanisms, and they provide strong evidence that more favorable effects on cardiac dysfunction and failure can be achieved by early initiation of MR blockade postinfarction. © 2011 Elsevier Inc.


PubMed | Klinik fuer Kardiologie und Angiologie
Type: Journal Article | Journal: Cardiovascular research | Year: 2012

Adverse cardiac remodelling is a major cause of morbidity and mortality following acute myocardial infarction (MI). Mechanical and neurohumoral factors involved in structural and molecular post-infarction remodelling were important targets in research and treatment for years. More recently, therapeutic strategies that address myocardial regeneration and pathophysiological mechanisms of infarct wound healing appear to be useful novel tools to prevent progressive ventricular dilation, functional deterioration, life-threatening arrhythmia, and heart failure. This review provides an overview of future and emerging therapies for cardiac wound healing and remodelling after MI.


PubMed | Klinik fuer Kardiologie und Angiologie
Type: Journal Article | Journal: Circulation | Year: 2011

Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MR(MLCCre)) that were generated with a conditional MR allele (MR(flox)) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter.Control (MR(flox/flox), MR(flox/wt)) and MR(MLCCre) mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MR(MLCCre) mice. Chronically infarcted MR(MLCCre) mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O(2)(-) production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MR(MLCCre) mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor-B and reduced apoptosis early after myocardial infarction.Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression.


PubMed | Klinik fuer Kardiologie und Angiologie
Type: Journal Article | Journal: Trends in cardiovascular medicine | Year: 2012

Clinical trials have clearly demonstrated that mineralocorticoid receptor (MR) blockade improves outcome in patients with chronic systolic heart failure and left ventricular dysfunction after myocardial infarction; however, the underlying mechanisms as well as the cell-specific functional role of MR activation are still under investigation. Extrarenal effects of MR blockade on cardiovascular extracellular matrix turnover and oxidative stress, on myocardial structural and electrical remodeling, and on sympathoadrenergic stimulation, platelet activation, endothelial dysfunction, and macrophage polarization appear to be important mechanisms. Recent scientific advances, involving mice with cardiomyocyte-restricted inactivation of the MR gene suggest that the clinical benefits of MR blocking therapy in myocardial infarction and heart failure are mediated largely via cardiomyocyte-dependent mechanisms, and they provide strong evidence that more favorable effects on cardiac dysfunction and failure can be achieved by early initiation of MR blockade postinfarction.


PubMed | Klinik fuer Kardiologie und Angiologie
Type: Journal Article | Journal: European journal of clinical investigation | Year: 2012

The classical view of aldosterone actions via the mineralocorticoid receptor (MR) limited to control of fluid balance and blood pressure homoeostasis has been progressively overcome by clinical and experimental evidence emphasizing the pleiotropic role of MR activation in the pathogenesis of cardiovascular disease. Clinical studies have shown the benefit of MR blockade in patients with left ventricular dysfunction and heart failure after myocardial infarction (MI), hypertension or diabetic nephropathy. Deleterious effects of MR activation include cardiac structural and electrical remodelling, cardiovascular fibrosis, inflammation and oxidative stress. Complexity of pathophysiological role of MR derives from the presence of circulating glucocorticoids at higher concentrations than aldosterone and the equal affinity of the MR for aldosterone, cortisol and corticosterone. Recent experimental studies using different animal models and genetic tools have deeply explored the cell-specific functional role of MR in cardiovascular pathology. This review addresses emerging preclinical studies as well as ongoing clinical trials regarding MR activation in MI and failure.

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