Heiko Kilter

Oxygen Free Radical Release in Human Failing Myocardium Is Associated With Increased Activity of Rac1-GTPase and Represents a Target for Statin Treatment

Background—Reactive oxygen species (ROS) contribute to the development of heart failure. A potential source of myocardial ROS is the NADPH oxidase, which is regulated by the small GTP-binding protein rac1. Isoprenylation of rac1 can be inhibited by statin therapy. Thus, we examined ROS and rac1 in human failing myocardium and tested their regulation by statins in vivo. Methods and Results—In human left ventricular myocardium from patients with ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM), NADPH oxidase activity was increased 1.5-fold compared with nonfailing controls (P <0.05, n=8). In failing myocardium, increased oxidative stress determined by measurements of lipid peroxidation and aconitase activity was associated with increased translocation of rac1 from the cytosol to the membrane. Pull-down assays revealed a 3-fold increase of rac1-GTPase activity in ICM and DCM. In parallel, membrane expression of the NADPH oxidase subunit p47phox, but not p67phox, was upregulated in failing compared with nonfailing myocardium. In right atrial myocardium from patients undergoing cardiac surgery who were prospectively treated with atorvastatin or pravastatin (40 mg/d, 4 weeks), rac1-GTPase activity was decreased to 67.9±12% and 65.6±13.8% compared with patients without statin (P <0.05, n=8). Both atorvastatin and pravastatin significantly reduced angiotensin II–stimulated but not basal NADPH oxidase activity. Conclusions—Failing myocardium of patients with DCM and ICM is characterized by upregulation of NADPH oxidase–mediated ROS release associated with increased rac1 activity. Oral statin treatment inhibits myocardial rac1-GTPase activity. These data suggest that extrahepatic effects of statins can be observed in humans and may be beneficial for patients with chronic heart failure.

Stabilization of β-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth

β-Catenin is a transcriptional activator that regulates embryonic development as part of the Wnt pathway and also plays a role in tumorigenesis. The mechanisms leading to Wnt-induced stabilization of β-catenin, which results in its translocation to the nucleus and activation of transcription, have been an area of intense interest. However, it is not clear whether stimuli other than Wnts can lead to important stabilization of β-catenin and, if so, what factors mediate that stabilization and what biologic processes might be regulated. Herein we report that β-catenin is stabilized in cardiomyocytes after these cells have been exposed to hypertrophic stimuli in culture or in vivo. The mechanism by which β-catenin is stabilized is distinctly different from that used by Wnt signaling. Although, as with Wnt signaling, inhibition of glycogen synthase kinase-3 remains central to hypertrophic stimulus-induced stabilization of β-catenin, the mechanism by which this occurs involves the recruitment of activated PKB to the β-catenin-degradation complex. PKB stabilizes the complex and phosphorylates glycogen synthase kinase-3 within the complex, inhibiting its activity directed at β-catenin. Finally, we demonstrate via adenoviral gene transfer that β-catenin is both sufficient to induce growth in cardiomyocytes in culture and in vivo and necessary for hypertrophic stimulus-induced growth. Thus, in these terminally differentiated cells, β-catenin is stabilized by hypertrophic stimuli acting via heterotrimeric G protein-coupled receptors. The stabilization occurs via a unique Wnt-independent mechanism and results in cellular growth.

c-Jun N-Terminal Kinases Mediate Reactivation of Akt and Cardiomyocyte Survival After Hypoxic Injury In Vitro and In Vivo

Akt is a central regulator of cardiomyocyte survival after ischemic injury in vitro and in vivo, but the mechanisms regulating Akt activity in the postischemic cardiomyocyte are not known. Furthermore, although much is known about the detrimental role that the c-Jun N-terminal kinases (JNKs) play in promoting death of cells exposed to various stresses, little is known of the molecular mechanisms by which JNK activation can be protective. We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide–dependent protein kinase. The reduction in Akt activity that is induced by JNK inhibition may have significant biological consequences, as we find that JNKs, acting via Akt, are critical determinants of survival in posthypoxic cardiomyocytes in culture. Furthermore, in contrast to selective p38–mitogen-activated protein kinase inhibition, which was cardioprotective in vivo, concurrent inhibition of both JNKs and p38–mitogen-activated protein kinases increased ischemia/reperfusion injury in the heart of the intact rat. These studies demonstrate that reactivation of Akt after resolution of hypoxia and ischemia is regulated by JNKs and suggest that this is likely a central mechanism of the myocyte protective effect of JNKs.

Deletion of cytosolic phospholipase A2 promotes striated muscle growth.

Generation of arachidonic acid by the ubiquitously expressed cytosolic phospholipase A2 (PLA2) has a fundamental role in the regulation of cellular homeostasis, inflammation and tumorigenesis. Here we report that cytosolic PLA2 is a negative regulator of growth, specifically of striated muscle. We find that normal growth of skeletal muscle, as well as normal and pathologic stress-induced hypertrophic growth of the heart, are exaggerated in Pla2g4a−/− mice, which lack the gene encoding cytosolic PLA2. The mechanism underlying this phenotype is that cytosolic PLA2 negatively regulates insulin-like growth factor (IGF)-1 signaling. Absence of cytosolic PLA2 leads to sustained activation of the IGF-1 pathway, which results from the failure of 3-phosphoinositide-dependent protein kinase (PDK)-1 to recruit and phosphorylate protein kinase C (PKC)-ζ, a negative regulator of IGF-1 signaling. Arachidonic acid restores activation of PKC-ζ, correcting the exaggerated IGF-1 signaling. These results indicate that cytosolic PLA2 and arachidonic acid regulate striated muscle growth by modulating multiple growth-regulatory pathways.

Leukocytoclastic vasculitis and myocardial infarction as presenting manifestations of infective endocarditis: a case report

In April 2009, a 32-year-old female patient was referred to our hospital with acute chest pain. She was diabetic, nicotine dependent and had a family history of coronary heart disease. The electrocardiogram showed a previously documented complete left bundle branch block. Cardiac troponin T was elevated (1.18 ng/ml, CK and CK-MB normal, LDH 333 U/l), C-reactive protein serum concentration was 157 mg/l (normal \ 5), white blood count was normal. Coronary angiography showed a thrombotic occlusion of the mid-LAD as culprit lesion (Fig. 1a, left panel). Additionally, a smooth lesion in the small PDA of the right coronary artery could be detected (Fig. 1a, right panel). The patient’s past medical history was complex. Aortic valve replacement with a biological prosthesis had been performed in 2006 due to infective endocarditis. Interestingly, 6 months before the acute coronary syndrome, i.e. in November 2008, the patient had been admitted to an external department with diffuse, non-symmetric arthralgia and a recurrent purpuric rash over her distal lower extremities. Hemorrhagic leukocytoclastic vasculitis had been diagnosed by skin biopsy (Fig. 1b). Laboratory tests conducted at that time had revealed a profound reduction in renal clearance (creatinine 2.4 mg/dl, cystatin C 3.3 mg/l, GFR 16-20 ml/min). Urinanalysis had shown proteinuria (0.84 g/24 h) and glomerular hematuria with detection of acanthocytes. These findings suggest that renal impairment had been caused by a glomerulonephritis. Monotherapy with prednisolone had been performed followed by chemotherapy with cyclophosphamid due to recurrence of symptoms after dose reduction of prednisolone. At the current admission to our department with an acute coronary syndrome, revascularization was performed by direct implantation of a bare metal stent in the midLAD. Because of the small vessel diameter there was no indication for a PCI of the PDA. However, the unusual lesion pattern in two distinct coronary vessels in a young patient with no further evidence of coronary heart disease was highly suspicious for coronary embolism, particularly in the light of the patient’s history of valve replacement 2 years earlier. During admission, the patient was recurrently subfebrile (\38 C), serum concentration of C-reactive protein remained elevated. Transesophageal echocardiography was performed twice. No typical endocarditic vegetations could be detected. However, thickening of the cusps of the bioprosthesis only two years after implantation as well as a mild aortic regurgitation were noticed. Immunosuppressant therapy was stopped. Serial blood cultures drawn at consecutive days yielded Granulicatella adiacens which proved to be highly sensitive to penicillin (MIC 0.004 mg/l). In one additional sample a b-lactamase positive, penicillin-resistant Staphylococcus aureus was obtained which was tested to be sensitive to oxacillin (MIC 0.25 mg/l). These positive microbiological results and the assumed embolic coronary event made the diagnosis of prosthetic valve endocarditis very likely and J. Poss M. Bohm H. Kilter (&) Universitatsklinikum des Saarlandes, Klinik fur Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Kirrberger Strase, 66421 Homburg/Saar, Germany e-mail: heiko.kilter@uks.eu

[Update cardiology 2006/2007].

This article reviews advances in cardiovascular medicine published last year. The following issues are reported in detail: (1) risk factors and lifestyle, (2) computed tomography in coronary artery disease, (3) revascularization in cardiogenic shock, (4) long-term anticoagulation in venous thrombosis, (5) anemia in heart failure, (6) optimism and cardiovascular death, (7) mortality after drug-eluting stents, (8) diabetes and cardiovascular disease, (9) new guidelines atrial fibrillation, (10) dopamine agonists and cardiac valve regurgitation, (11) beta-blockers and hypertension, (12) angiotensin-converting enzyme inhibitors and aortic rupture, (13) statin therapy, (14) adherence to pharmacotherapy.ZusammenfassungDer vorliegende Artikel soll einen Überblick über nennenswerte neue Erkenntnisse in der kardiovaskulären Medizin verschaffen, die von allgemeinem Interesse sind und im vergangenen Jahr publiziert wurden. Auf folgende Themen wird im Einzelnen eingegangen: 1. Risikofaktoren und Lifestyle, 2. CT-Diagnostik der koronaren Herzkrankheit, 3 Revaskularisation bei kardiogenem Schock, 4. Langzeitantikoagulation nach Thrombose, 5. Anämie und Herzinsuffizienz, 6. Optimismus und kardiovaskulärer Tod, 7. Überleben mit Drug-eluting Stents, 8. Diabetes mellitus und Herz- Kreislauf-Erkrankungen, 9. die neuen Leitlinien Vorhofflimmern, 10. Parkinson- Mittel und Herzklappeninsuffizienzen, 11. β−Blocker und Bluthochdrucktherapie, 12. ACE-Hemmer bei Aortenaneurysma, 13. Statintherapie, 14. Einnahmetreue bei Medikamenten.AbstractThis article reviews advances in cardiovascular medicine published last year. The following issues are reported in detail: (1) risk factors and lifestyle, (2) computed tomography in coronary artery disease, (3) revascularization in cardiogenic shock, (4) long-term anticoagulation in venous thrombosis, (5) anemia in heart failure, (6) optimism and cardiovascular death, (7) mortality after drug-eluting stents, (8) diabetes and cardiovascular disease, (9) new guidelines atrial fibrillation, (10) dopamine agonists and cardiac valve regurgitation, (11) β-blockers and hypertension, (12) angiotensin-converting enzyme inhibitors and aortic rupture, (13) statin therapy, (14) adherence to pharmacotherapy.

Aktuelle Kardiologie 2006/2007

This article reviews advances in cardiovascular medicine published last year. The following issues are reported in detail: (1) risk factors and lifestyle, (2) computed tomography in coronary artery disease, (3) revascularization in cardiogenic shock, (4) long-term anticoagulation in venous thrombosis, (5) anemia in heart failure, (6) optimism and cardiovascular death, (7) mortality after drug-eluting stents, (8) diabetes and cardiovascular disease, (9) new guidelines atrial fibrillation, (10) dopamine agonists and cardiac valve regurgitation, (11) beta-blockers and hypertension, (12) angiotensin-converting enzyme inhibitors and aortic rupture, (13) statin therapy, (14) adherence to pharmacotherapy.ZusammenfassungDer vorliegende Artikel soll einen Überblick über nennenswerte neue Erkenntnisse in der kardiovaskulären Medizin verschaffen, die von allgemeinem Interesse sind und im vergangenen Jahr publiziert wurden. Auf folgende Themen wird im Einzelnen eingegangen: 1. Risikofaktoren und Lifestyle, 2. CT-Diagnostik der koronaren Herzkrankheit, 3 Revaskularisation bei kardiogenem Schock, 4. Langzeitantikoagulation nach Thrombose, 5. Anämie und Herzinsuffizienz, 6. Optimismus und kardiovaskulärer Tod, 7. Überleben mit Drug-eluting Stents, 8. Diabetes mellitus und Herz- Kreislauf-Erkrankungen, 9. die neuen Leitlinien Vorhofflimmern, 10. Parkinson- Mittel und Herzklappeninsuffizienzen, 11. β−Blocker und Bluthochdrucktherapie, 12. ACE-Hemmer bei Aortenaneurysma, 13. Statintherapie, 14. Einnahmetreue bei Medikamenten.AbstractThis article reviews advances in cardiovascular medicine published last year. The following issues are reported in detail: (1) risk factors and lifestyle, (2) computed tomography in coronary artery disease, (3) revascularization in cardiogenic shock, (4) long-term anticoagulation in venous thrombosis, (5) anemia in heart failure, (6) optimism and cardiovascular death, (7) mortality after drug-eluting stents, (8) diabetes and cardiovascular disease, (9) new guidelines atrial fibrillation, (10) dopamine agonists and cardiac valve regurgitation, (11) β-blockers and hypertension, (12) angiotensin-converting enzyme inhibitors and aortic rupture, (13) statin therapy, (14) adherence to pharmacotherapy.

Aktuelle Kardiologie 2006/2007@@@Update Cardiology 2006/2007: Jahresrückblick und Ausblick

This article reviews advances in cardiovascular medicine published last year. The following issues are reported in detail: (1) risk factors and lifestyle, (2) computed tomography in coronary artery disease, (3) revascularization in cardiogenic shock, (4) long-term anticoagulation in venous thrombosis, (5) anemia in heart failure, (6) optimism and cardiovascular death, (7) mortality after drug-eluting stents, (8) diabetes and cardiovascular disease, (9) new guidelines atrial fibrillation, (10) dopamine agonists and cardiac valve regurgitation, (11) beta-blockers and hypertension, (12) angiotensin-converting enzyme inhibitors and aortic rupture, (13) statin therapy, (14) adherence to pharmacotherapy.ZusammenfassungDer vorliegende Artikel soll einen Überblick über nennenswerte neue Erkenntnisse in der kardiovaskulären Medizin verschaffen, die von allgemeinem Interesse sind und im vergangenen Jahr publiziert wurden. Auf folgende Themen wird im Einzelnen eingegangen: 1. Risikofaktoren und Lifestyle, 2. CT-Diagnostik der koronaren Herzkrankheit, 3 Revaskularisation bei kardiogenem Schock, 4. Langzeitantikoagulation nach Thrombose, 5. Anämie und Herzinsuffizienz, 6. Optimismus und kardiovaskulärer Tod, 7. Überleben mit Drug-eluting Stents, 8. Diabetes mellitus und Herz- Kreislauf-Erkrankungen, 9. die neuen Leitlinien Vorhofflimmern, 10. Parkinson- Mittel und Herzklappeninsuffizienzen, 11. β−Blocker und Bluthochdrucktherapie, 12. ACE-Hemmer bei Aortenaneurysma, 13. Statintherapie, 14. Einnahmetreue bei Medikamenten.AbstractThis article reviews advances in cardiovascular medicine published last year. The following issues are reported in detail: (1) risk factors and lifestyle, (2) computed tomography in coronary artery disease, (3) revascularization in cardiogenic shock, (4) long-term anticoagulation in venous thrombosis, (5) anemia in heart failure, (6) optimism and cardiovascular death, (7) mortality after drug-eluting stents, (8) diabetes and cardiovascular disease, (9) new guidelines atrial fibrillation, (10) dopamine agonists and cardiac valve regurgitation, (11) β-blockers and hypertension, (12) angiotensin-converting enzyme inhibitors and aortic rupture, (13) statin therapy, (14) adherence to pharmacotherapy.