Holger Diedrichs

Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure

Cardiac hypertrophy may initiate progression to a compromised cardiac function. While the clinical consequences of hypertrophy are well understood, only little is known about the underlying molecular pathways. As reported from animal experiments, the Ca2+‐calmodulin activated phosphatase calcineurin and its downstream transcriptional effector NFAT have been implicated as transducers of the hypertrophic response.

Prognostic impact of NT-proBNP and renal function in comparison to contemporary multi-marker risk scores in heart failure patients.

Multi‐marker risk scores accurately predict prognosis in heart failure patients but calculation is complex.

Mechanisms of Ca2+-Dependent Calcineurin Activation in Mechanical Stretch-Induced Hypertrophy

Pressure overload is the major stimulus for cardiac hypertrophy. Accumulating evidence suggests an important role for calcium-induced activation of calcineurin in mediating hypertrophic signaling. Hypertrophy is an important risk factor for cardiovascular morbidity and mortality. We therefore employed an in vitro mechanical stretch model of cultured neonatal cardiomyocytes to evaluate proposed mechanisms of calcium-induced calcineurin activation in terms of inhibition of calcineurin activity and hypertrophy. The protein/DNA ratio and ANP gene expression were used as markers for stretch-induced hypertrophy. Stretch increased the calcineurin activity, MCIP1 gene expression and DNA binding of NFATc as well as the protein/DNA ratio and ANP mRNA in a significant manner. The specific inhibitor of calcineurin, cyclosporin A, inhibited the stretch-induced increase in calcineurin activity, MCIP1 gene expression and hypertrophy. The L-type Ca2+ channel blocker nifedipine and a blocker of the Na+/H+ exchanger (cariporide) both suppressed stretch-dependent enhanced calcineurin activity and hypertrophy. Also application of a blocker of the Na+/Ca2+ exchanger (KB-R7943) was effective in preventing calcineurin activation and increases in the protein/DNA ratio. Inhibition of capacitative Ca2+ entry with SKF 96365 was also sufficient to abrogate calcineurin activation and hypertrophy. The blocker of stretch-activated ion channels, streptomycin, was without effect on stretch-induced hypertrophy and calcineurin activity. The present work suggests that of the proposed mechanisms for the calcium-induced activation of calcineurin (L-type Ca2+ channels, capacitative Ca2+ entry, Na+/H+ exchanger, Na+/Ca2+ exchanger and stretch-activated channels) all but stretch-activated channels are possible targets for the inhibition of hypertrophy.

NT-pro-BNP for differential diagnosis in patients with syncope

BACKGROUND Syncope is a frequent diagnosis and establishing the etiology is often elaborate. Aim of this study was to evaluate the diagnostic value of NT-pro-BNP in patients with syncope. METHODS NT-pro-BNP was assessed in 61 patients admitted for syncope to our cardiological department of the University hospital Cologne, Germany. RESULTS 16 patients (26.2%) had neurally-mediated syncope, 9 (14.8%) had orthostatic syncope, 12 (19.7%) had cardiac arrhythmias, 8 (13.1%) had structural cardiac/cardiopulmonary disease, 2 patients (3.3%) had cerebrovascular disease, 3 (4.9%) had non-syncopal attack and in 11 (18%) patients the cause remained unknown. Patients with cardiac syncope had significantly higher NT-pro-BNP values (514 IQR 286-1154 pg/ml) than patients with non-cardiac cause (182 IQR 70-378 pg/ml, p=0.001). NT-pro-BNP at a cut-off of 164 pg/ml identified patients with cardiac syncope and patients requiring interventional cardiological therapy with a sensitivity of 90% and 93.8%, a specificity of 48.8% and 46.7% and a negative predictive value of 91% and 95.5%. NT-pro-BNP pre-testing could save 45% of the Holter ECGs, 83% of the telemetry monitoring, 47% of stress tests, 49% of echocardiographies, 67% of coronary angiographies and 43% of electrophysiological examinations. CONCLUSIONS NT-pro-BNP assessment was helpful in differentiating cardiac from non-cardiac syncope. Further studies are needed to define the role of NT-pro-BNP in the diagnostic algorithm of syncope.

Activation of the calcineurin/NFAT signalling cascade starts early in human hypertrophic myocardium.

Cardiac hypertrophy is an independent risk factor for heart failure. Recent studies on gene regulation of proteins have involved intracellular Ca2+ homeostasis. The Ca2+-sensitive phosphatase, calcineurin, is one potential regulator of the hypertrophic response, so we aimed to investigate the calcineurin-dependent signal pathway at different stages of hypertrophy in human myocardium. We found the calcineurin pathway to be significantly activated in hypertrophic compared with non-hypertrophic myocardium as demonstrated by increased calcineurin activity and expression of calcineurin A-β and B, and GATA-4, and a shift of phosphorylated cytoplasmic NFAT-3 into the nucleus as dephosphorylated nuclear NFAT-3. There was a tendency for these changes to be more pronounced in the decompensated compared with the compensated hypertrophic myocardium. The present study provides evidence for significant activation of the Ca2+-triggered calcineurin pathway in hypertrophic humans. Already present in compensated hypertrophy it showed a tendency to a further increase following transition to decompensated hypertrophy.

In vivo uptake of azithromycin in human coronary plaques

Ten patients with symptomatic coronary artery disease received oral azithromycin for 3 days and underwent directional atherectomy on the third day. Azithromycin was found in all plaque samples with a median concentration of 284 ng/ml (95% confidence interval 163 to 517 ng/ml).

An increase in HbA1c after percutaneous coronary intervention raises the risk for restenosis in patients without Type 2 diabetes mellitus

Aims  The influence of dynamic changes in glycated haemoglobin (HbA1c) on restenosis after elective percutaneous coronary intervention (PCI) in patients without diabetes has not been analysed. Therefore, the rate of restenosis was investigated after elective PCI in 101 consecutive patients without diabetes mellitus in relation to dynamic changes of HbA1c levels.

Inefficacy of different strategies to improve guideline awareness – 5-year follow-up of the hypertension evaluation project (HEP)

BackgroundIn spite of numerous guidelines for evidence based diagnostic and therapy adequate knowledge of current recommendations is disappointingly low. In the Hypertension Evaluation Project (HEP I) we showed that awareness of national hypertension guidelines under German practitioners was less than 25% in the year 2000. This indicates the need for efficient strategies to relevantly improve guideline awareness.MethodsTo asses different tools for amending guideline knowledge we used three strategies (guideline in print, interactive guideline, expert seminars) to train 8325 randomised physicians, who had participated in the HEP I trial. Guideline knowledge of the trained physicians was again tested with the HEP questionnaire and compared to a control group of HEP I physicians.ResultsThe return rate of questionnaires was 57.9% without a significant distinction between the groups. Overall guideline awareness was still low but remarkably improved compared to the results of HEP I (37.1% vs. 23.7%, p < 0.0001). There was no difference between the trained physicians and the control group (35.8% and 35.9% vs. 39.7%, p = n.s.).ConclusionWe investigated the influence of different strategies to improve guideline awareness among German physicians. None of our interventions (guideline in print, interactive guideline, expert seminars) brought a notable benefit compared to control group. However, overall knowledge of guideline contents increased from 23.7% to 37.1% over five years. Therefore, other probably multimodal interventions are necessary to significantly improve guideline awareness beyond spontaneous advancement.Trial RegistrationISRCTN53383289

Verbesserte myokardiale Durchblutung nach epiduraler Rückenmarkstimulation bei therapierefraktärer Angina pectoris

Zusammenfassung.Hintergrund: Es gibt einen zunehmenden Anteil von Patienten mit koronarer Herzerkrankung und Angina-pectoris-Beschwerden, bei denen trotz großer Fortschritte im operativen und katheterinterventionellen Bereich eine Revaskularisierung nicht möglich ist. Therapie: Eine kürzlich veröffentlichte Übersicht der Arbeitsgruppe zur Behandlung der refraktären Angina pectoris der Europäischen Gesellschaft für Kardiologie (ESC) führt die Neurostimulation an erster Stelle der alternativen Therapiemöglichkeiten für diese Patienten an. Dabei handelt es sich um ein bereits seit vielen Jahren bekanntes Verfahren, welches jedoch in der Bundesrepublik Deutschland, trotz großer Erfahrungen im europäischen Ausland, bisher nur vereinzelt angewendet wurde. Die vorliegenden Studien belegen, dass es sich dabei um eine effiziente Therapie handelt. Durch Reduktion der Angina-pectoris-Symptomatik und konsekutive Zunahme der körperlichen Leistungsfähigkeit wird eine entscheidende Verbesserung der Lebensqualität erzielt. Erste Daten aus einer eigenen Studie zeigen, dass sich auch die myokardiale Durchblutung unter Neurostimulation im Langzeitverlauf verbessert. Dies könnte an einer verbesserten Kollateralisierung durch die gesteigerte Belastbarkeit liegen oder aber ein direkter Effekt der Therapie sein. Schlussfolgerung: Wir sehen in Übereinstimmung mit den Empfehlungen der ESC die Neurostimulation als Therapiemöglichkeit der ersten Wahl für Patienten mit refraktärer Angina pectoris an. Konventionelle und kausal eingreifende Therapieverfahren sollen selbstverständlich nicht durch eine Neurostimulation ersetzt werden. Eine strenge Indikationsstellung ist daher unumgänglich.Abstract.Background: In spite of great progresses in surgical and catheter interventional techniques there is an increasing number of patients with coronary heart disease not suitable for these conventional treatment strategies. Therapy: A recent review of the Study Group on the treatment of refractory angina pectoris of the European Society of Cardiology (ESC) recommends spinal cord stimulation (SCS) as first-line therapy. SCS is a well-known and often used therapy for refractory angina in other European countries but not in Germany. The present studies show that SCS is an efficient therapy. By reduction of angina symptoms and a consecutive increase of exercise capacity, the patients experience a great improvement in quality of life. In addition, recent data of our own study suggest a significant decrease in myocardial ischemia in patients under SCS. This might be a direct effect of SCS or due to a better collateralization because of the improved exercise capacity. Conclusion: In agreement with the study group of the ESC, we would recommend SCS as first-line therapy for refractory angina pectoris. As a matter of course, conventional treatment strategies should not be replaced by SCS. Hence, a strict evaluation before implanting a SCS device is indispensable.

Delta-glycated hemoglobin: A novel independent risk factor for cardiovascular events in patients without diabetes mellitus

Background: A single measurement of glycated hemoglobin (HbA1c) is a weak predictor for cardiovascular events in patients without Type 2 diabetes mellitus. We hypothesized that dynamic changes in HbA1c (Delta-HbA1c) would better predict cardiovascular outcome than a single value. Methods: In 99 consecutive patients with stable coronary artery disease (CAD) and without diabetes mellitus who were seen twice in our outpatient clinic (4–6 months apart) in 1998, Delta-HbA1c (follow-up HbA1c–baseline HbA1c) was assessed. Between August and September 2007 (mean observation period 9.1 yr), patients and their physicians were contacted by telephone to evaluate the incidence of cardiovascular endpoints. The combined primary endpoint of our study was defined as the incidence of myocardial infarction, stroke or death from any cause. The endpoints were validated by chart review. Results: Multivariate analysis demonstrated that the change of HbA1c between first and second examination in 1998 was the most powerful parameter for prediction of the combined primary endpoint in the next 9 yr. The hazard ratio was 5.03 [95% confidence interval (CI) 1.4–17.9] for any increase in HbA1c and 1.99 (95%CI 1.3–3.0) for an HbA1c increase of 0.3%. In addition, Kaplan-Meier survival analysis showed a significant association between endpoint-free survival and dynamic changes in HbA1c. Conclusions: Hence, changes in the glucometabolic milieu within 4–6 months calculated by the difference of two values of HbA1c affect the long-term prognosis of patients with CAD but without diabetes mellitus.