[Defi catches on : Implementation of a curriculum for resuscitation in secondary schools]. / Defi macht Schule : Implementierung eines Curriculums zum Thema Reanimation an weiterführenden Schulen.

BACKGROUND: Sudden cardiac arrest is still one of the most frequent causes of death. Teaching resuscitation in schools was already successfully implemented in Scandinavian countries. Following a recommendation of the conference of german stateministers of education in June 2014, additional tuition for resuscitation is to be implemented in german schools starting in seventh grade. METHODS: The present study aimed to assess the level of knowledge of seventh grade students in the field of life support and to implement curricular standards for resuscitation courses in secondary schools. Using a standardized questionnaire, students in seventh grade of five schools in Cologne were interrogated about their knowledge on resuscitation and defibrillation. This assessment was taken as basis for developing a curricular teaching concept by the Cologne heart centre in cooperation with the department of biology and technical didactics at the University of Cologne. This tutorial concept was integrated in scholar plans for the first time in the school year 2014/2015. At the end of the school year the students' knowledge got reevaluated. RESULTS: As expected, the technical knowledge of the interviewed students is low, however confidence in their own abilities is high. Most of the interviewed persons would be willing to perform chest compressions (72,26%) and dare using an automated external defibrillator (AED, 64,38%). The exact position of defibrillator pads cannot be precisely indicated by most students (8,40%), compression point, -depth and -frequency are known by just one third of students. Already one-time performance of the live-saving lesson resulted in a clear increase of knowledge about resuscitation. CONCLUSIONS: The willingness to perform resuscitation measures and confidence in their own abilities are high in seventh grade students. Therefore, the recommendation of the conference of german stateministers of education in June 2014 addresses the right target group. Long-term success of the presented educational concept will be analysed and reported in a longitudinal study.

Changes in neuron-specific enolase are more suitable than its absolute serum levels for the prediction of neurologic outcome in hypothermia-treated patients with out-of-hospital cardiac arrest.

BACKGROUND: To determine neurologic outcome in patients with out-of-hospital cardiac arrest (OHCA) and treatment with mild therapeutic hypothermia (MTH). METHODS: Seventy-three consecutive OHCA patients treated with MTH were retrospectively analyzed. Serum neuron-specific enolase (NSE) was measured 24, 48, and 72 h after admission. In patients with no motor response 48 h after termination of analgosedation (n = 40), clinical neurological examination and evoked potentials (EPs) were determined. Neurological outcome was assessed after 2 months based on the cerebral performance categories (CPC), and categorized as good (CPC 1-3) or poor (CPC 4 and 5). RESULTS: Forty-three patients had a CPC score of 1-3 and 30 patients had a CPC 4-5. The best predictive value for poor neurologic outcome was an increase of NSE by ≥4.3 ng/mL between day 1 and day 2 (sensitivity 80 %, specificity 100 %, positive predictive value (PPV) 100 %, negative predictive value 86 %). Absolute NSE values were less reliable in the prediction of poor outcome with the highest sensitivity (88 %) and specificity (95 %) if values reached ≥36.3 ng/mL on day 3. Somatosensory EPs (SSEPs) showed a specificity of 100 % and PPV of 100 %; however, sensitivity for evoked potentials was low (29 %). Intriguingly, two initially comatose patients with excessive NSE values (24 h NSE: 101 and 256 ng/mL, and 48 h NSE: 93 and 110 ng/mL, respectively) had physiological SSEPs and regained a CPC score of 1. CONCLUSION: In patients treated with MTH after OHCA changes in NSE are more suitable than its absolute serum levels for the prediction of poor neurologic outcome. Since unequivocal prediction of poor neurologic outcome is of utmost importance in these patients the decision to limit therapy must be based on several prediction tools with the highest PPV and specificity including SSEPs.

The G protein Gα11 is essential for hypertrophic signalling in diabetic myocardium.

AIMS/HYPOTHESIS: Pathological cardiac hypertrophy is an early phenotype in both types 1 and 2 diabetes. The primary stimulus for hypertrophic growth in diabetes is yet unknown and may involve neurohumoral stimulation of Gq-coupled receptors as well as direct glucose-dependent mechanisms. To discriminate between these hypertrophic stimuli we analyzed hypertrophic signalling pathways in wildtype and Gα11-knockout mice. METHODS: Experimental diabetes was induced in wildtype and knockout mice by intraperitoneal injection of streptozotocin. 8 weeks after induction of diabetes myocardial function and structure was assessed by echocardiography before sacrifice. To identify prohypertrophic signalling pathways expression and translocation of protein kinase C isoforms α, ßII, δ, ε and ζ were analyzed by immunohistochemical staining and immunoblot analysis after tissue fractionation. Changes in calcineurin signalling were identified by immunoblot analysis and functional assays. Expression levels of transcription factors GATA4 and NF-κB were quantified by real-time RT-PCR. RESULTS: Diabetic wildtype mice developed myocardial hypertrophy with preserved cardiac function. Calcineurin signalling was not different between the two groups. However, diabetic wildtype mice showed increased protein levels of PKC-α and PKC-ζ, translocation of PKC-α, -δ and -ε to cellular membranes and higher levels of NF-κB expression. In contrast, diabetic Gα11-knockout mice showed no altered phenotype and no changes in NF-κB or PKC expression, although translocation of PKC-ε occurred as in wildtypes. CONCLUSIONS: Gα11 is essential for the development of cardiac hypertrophy in type 1-diabetes. Stimulation of hypertrophic signalling through PKC-α, PKC-δ, PKC-ζ, and NF-κB appears to be receptor-dependent, whereas PKC-ε is activated by hyperglycemia, independent of Gα11.

Fluid therapy and acute kidney injury in cardiogenic shock after cardiac arrest.

AIM OF THE STUDY: It has recently been suggested that acute kidney injury (AKI) may strongly be influenced by post-resuscitation disease and cardiogenic shock (CS), and may not just be a consequence of cardiac arrest and time without spontaneous circulation. AKI also has been suggested as a strong independent predictor of in-hospital mortality. Therefore the present study aimed at investigating the effect of fluid management on the incidence of AKI in patients with cardiogenic shock after cardiac arrest treated by mild therapeutic hypothermia. METHODS: Fluid therapy and the incidence of acute kidney injury (AKI) was retrospectively reviewed in 51 patients with cardiogenic shock after cardiac arrest comparing patients with and without hemodynamic (PPV, SVV) and volumetric (ELWI, GEDI) monitoring. RESULTS: There was no significant difference in baseline or cardiac arrest characteristics between hemodynamic monitored patients and conventional monitored patients. 28 patients were monitored by standard monitoring, in 23 patients monitoring was complemented by a PICCO system. In the first 24h of treatment the total amount of fluid was significantly higher in patients under PICCO monitoring compared to conventional monitoring (4375±1285ml vs. 5449±1438ml, p=0.007). This was associated with a significant reduction in the incidence of AKI (RIFLE 'I'/'F': PICCO-group: 1 (4.3%) vs. conventional group 8 (28.6%), p=0.03). CONCLUSION: The presented data suggest that volume therapy guided by volumetric (ELWI, GEDI) and arterial waveform derived variables (PPV, SVV) can reduce the incidence of AKI in patients with cardiogenic shock after cardiac arrest treated with mild therapeutic hypothermia.

Aldosterone induces electrical remodeling independent of hypertension.

BACKGROUND: Treatment of heart failure patients with aldosterone antagonists has been shown to reduce the occurrence of sudden cardiac death. Therefore we aimed at determining the consequences of chronic exposure to aldosterone and the aldosterone antagonists eplerenone and spironolactone on the electrophysiological properties of the heart in a rat model. METHODS AND RESULTS: Male Wistar rats were chronically treated (4weeks) with aldosterone (ALD) via an osmotic minipump. Spironolactone (SPI) or eplerenone (EPL) was administered with the rat chow. ALD treated animals developed left ventricular hypertrophy, prolonged QT-intervals, a higher rate of ventricular premature beats and non-sustained ventricular tachycardia despite normal blood pressure values. Spironolactone and eplerenone were both able to inhibit the alterations. Left-ventricular mRNA expressions of Kv4.2 and Kv4.3 (Ito), Kv1.5 (IKur), Kir2.1 and Kir2.3 (IK1) and of Cav1.2 (L-type Ca(2+) channel) were significantly down-regulated in ALD. Correspondingly, the protein expressions of subunits Kv1.5, Kir2.3 and Cav1.2 were significantly decreased. A diminished calcineurin activity and mRNA expression of the Aß subunit of calcineurin were found in ALD, which was insensitive to aldosterone antagonists. CONCLUSIONS: Chronic aldosterone-overload induces blood pressure independent structural and electrical remodeling of the myocardium resulting in an increased risk for malignant ventricular arrhythmias.

Spironolactone prevents aldosterone induced increased duration of atrial fibrillation in rat.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. The Renin-Angiotensin-Aldosterone-System plays a major role for the atrial structural and electrical remodelling. Recently elevated aldosterone levels have been suggested to increase the risk for the development of AF. METHODS: Rats were treated with aldosterone by means of an osmotic minipump (0.5µg/h) over a period of 4 weeks. AF was induced by transesophageal burst pacing. Action potentials (AP) were recorded from left atrial preparations with microelectrodes. Atrial collagen was quantified by histological studies. RESULTS: Aldosterone treatment resulted in hypertrophy as indicated by an increased ratio of heart weight/tibia length and doubled the time until the AF converted spontaneously into sinus rhythm (85.8±13.4 s vs. 38.3±6.9 s, p<0.01). This was associated with a significant shortening of the AP (APD90 26.2±1.1 vs. 31.2±1.9, p<0.05) and an increased protein expression of Kir2.1 and Kv1.5. Atrial collagen deposition was significantly greater in aldosterone-treated rats. The alterations could be prevented by additional application spironolactone. CONCLUSIONS: The results of the present study suggest that in addition to the structural remodelling aldosterone also promotes AF by altering repolarising potassium currents leading to action potential shortening.

MRI in patients with pacemakers: overview and procedural management.

BACKGROUND: Magnetic resonance imaging (MRI) is generally contraindicated for patients with a pacemaker (PM) or implantable cardiac defibrillator (ICD), because of the risk of life-threatening interference with the device. Nevertheless, the question whether to perform MRI despite the presence of these devices can still arise when MRI is vitally indicated. In some hospitals, special precautionary measures are taken so that MRI can be performed in such cases. METHODS: This review is based on the authors' experience in 42 patients who underwent MRI at our university hospital, on the pertinent literature, and on the recommendations of medical societies. RESULTS: Because of its excellent image quality, MRI is often an indispensable diagnostic tool. Structured multidisciplinary management enables it to be performed safely even in patients with a PM or ICD. Pre- and post-MRI checks of the device are recommended, as well as extensive monitoring and the availability of the necessary personnel to deal with an emergency. In general, the pacing and defibrillator functions should be deactivated; for pacemaker-dependent patients, the asynchronous pacing mode should be activated. No serious incidents have occurred when these precautions have been observed, either among our own patients or in the literature. Newer PM systems have been approved for MRI scanning under certain conditions. CONCLUSION: In patients with a PM or ICD, the benefit of MRI may far outweigh its risks if the indication has been established for the particular patient as an interdisciplinary decision and if the appropriate precautions are observed during scanning. Now that newer PM systems have been approved for MRI scanning, the problem seems close to being solved.

Mild therapeutic hypothermia in cardiogenic shock syndrome.

OBJECTIVE: Mortality in patients with cardiogenic shock after out-of-hospital cardiac arrest remains high despite advances in resuscitation and early revascularization strategies. Recent studies suggest a reduced mortality in survivors of cardiac arrest subjected to mild therapeutic hypothermia, but the underlying mechanisms are not yet clear. Because positive hemodynamic effects of mild therapeutic hypothermia have been suggested, we aimed at testing the hypothesis that patients in cardiogenic shock might benefit from mild therapeutic hypothermia. METHODS: Hemodynamic effects of mild therapeutic hypothermia in 20 consecutive patients admitted in cardiogenic shock after successful resuscitation from out-of-hospital cardiac arrest were investigated. A historic normothermic control group was matched (one-to-one) by means of a propensity score. Patients were cooled to 33°C for 24 hrs using an endovascular cooling device and hemodynamic variables were continuously recorded by means of pulse contour analysis. Cardiac performance was determined by echocardiography. RESULTS: Mild therapeutic hypothermia induced a significant decrease in heart rate from 74 to 64 beats per minute. Despite the reduction in heart rate, cardiac index remained unchanged under mild therapeutic hypothermia likely due to an increase in ejection fraction from 43 ± 4% to 55 ± 4%. Mean arterial pressure increased rapidly from 75 ± 2 mm Hg to 84 ± 3 mm Hg (p = .001) upon induction of hypothermia paralleled by an initial increase in systemic vascular resistance. Accordingly, patients with mild therapeutic hypothermia required lower cumulative doses of vasopressors and inotropes. CONCLUSIONS: We conclude that in cardiogenic shock mild therapeutic hypothermia provides circulatory support and an increase in systemic vascular resistance that leads to reduced vasopressor use and may result in lower oxygen consumption. These findings suggest that mild therapeutic hypothermia could be a therapeutic option in hemodynamically unstable patients independent of cardiac arrest and further randomized clinical studies are needed.

Mortality in a cardiac intensive care unit.

OBJECTIVE: There are no reliable data on mortality and morbidity of adult patients in modern university-based cardiac intensive care units. Therefore, the present study was aimed to provide complete data in respect to mortality and morbidity of all patients admitted between 1 January 2008 and 31 December 2009 to the newly opened cardiac intensive care unit of the Heart Centre of the Cologne University Hospital. METHODS: All patients admitted to the 6-bed intensive care unit of the Heart Centre of the University of Cologne between January 1 2008 and December 31 2009 were included in this study. RESULTS: A total of 684 patients were investigated. The majority of patients (71.1%) were male. The overall in-hospital mortality was 32.5%. The most frequent diagnosis was acute coronary syndrome (43.6%). Coronary angiography was performed in 45.5% of all patients. Cardiopulmonary resuscitation was the reason for admission in 30.8%, the in-hospital mortality of those patients (46.0%) was much higher compared to the overall mortality. CONCLUSIONS: Our data demonstrate that despite state-of-the-art university-based intensive care medicine with modern equipment the mortality remains high. These findings will help in calculating the resources required to meet the increasing demand for intensive care medicine.

Hyperaldosteronism is associated with a decrease in number and altered growth factor expression of endothelial progenitor cells in rats.

BACKGROUND: Aldosterone plays a role in hypertension, the pathogenesis of heart failure and vascular injury. However, little information exists about the possible influence of aldosterone on bone marrow derived endothelial progenitor cells (EPC), which are involved in the repair of damaged endothelium. This study was designed to determine the long- term in vivo influence of aldosterone on the number of EPC. METHODS: Male Wistar rats were equipped with a subcutaneous pump which released aldosterone (n=20) or placebo (n=20) over 28 days. The animals were either fed with or without the aldosterone antagonist spironolactone (each n=10). EPC were identified by the uptake of ac-LDL and BS-1. The expression of VEGF-2 receptor, VEGF, HGF, SDF1 and the mineralocorticoid receptor (MR) in EPC was assessed by quantitative PCR. Finally, VEGF concentration was measured in the serum of all animals by ELISA. RESULTS: The total number of EPC was significantly lowered by chronic aldosterone treatment. Spironolactone compensated the effect and lead to a 2-fold increase. While the SDF1 mRNA was not affected by aldosterone, HGF, MR2 and VEGF receptor mRNA were significantly downregulated in EPC. Strikingly spironolactone not only leads to increases in the mRNA expression in hyper-aldosteronemic animals but also exhibited significant increases above the control levels. CONCLUSION: The present data indicate that high levels of aldosterone impair the function and reduce the numbers of EPC and lead to a downregulation of VEGF and the VEGF receptor in vivo. Spironolactone antagonized these effects. MR blockade by spironolactone may therefore represent a future tool to enhance the response to cell based therapy.

Sarcoplasmic Ca2+ release is prolonged in nonfailing myocardium of diabetic patients.

Background Asymptomatic diabetic patients have a high incidence of clinically unrecognized left ventricular dysfunction with an abnormal cardiac response to exercise. We, therefore, examined subclinical defects in the contraction-relaxation cycle and intracellular Ca(2+) regulation in myocardium of asymptomatic type 2 diabetic patients. Methods Alterations in the dynamics of the intracellular Ca(2+) transient and contractility were recorded in right atrial myocardium of type 2 diabetic patients and non-diabetic control tissue loaded with fura-2. In order to gain an insight into mechanisms underlying the altered Ca(2+) handling in diabetic myocardium levels of mRNA, protein expression and phosphorylation of key proteins in sarcoplasmic Ca(2+) handling were determined. Results In isolated atrial trabeculae of diabetic myocardium the rise of systolic Ca(2+) was significantly prolonged, but relaxation of the Ca(2+) transient was unaltered compared to control tissue. Accordingly, the levels of expression of mRNA and protein of the Ca(2+) release channel (RyR2) of the sarcoplasmic reticulum were reduced by 68 and 22%, respectively. Endogenous phosphorylation of RyR2 by protein kinases C, however, was increased by 31% in diabetic myocardium, as assessed by the back-phosphorylation technique. Levels of expression of SERCA2 and phospholamban were unaltered between both groups. Conclusions Intracellular Ca(2+) release is prolonged in non-failing myocardium of type 2 diabetic patients and this may be primarily due to a decreased expression of RyR2. This defective Ca(2+) release may represent an early stage of ventricular dysfunction in type 2 diabetes and would favor the abnormal response to exercise frequently observed in asymptomatic diabetic patients.

A simple device to apply equibiaxial strain to cells cultured on flexible membranes.

The biomechanical environment to which cells are exposed is important to their normal growth, development, interaction, and function. Accordingly, there has been much interest in studying the role of biomechanical forces in cell biology and pathophysiology. This has led to the introduction and even commercialization of many experimental devices. Many of the early devices were limited by the heterogeneity of deformation of cells cultivated in different locations of the culture plate membranes and were also attached with complicated technical/electronic efforts resulting in a restriction of the reproducibility of these devices. The objective of this study was to design and build a simple device to allow the application of dose-dependent homogeneous equibiaxial static stretch to cells cultured on flexible silicone membranes to investigate biological and biomedical questions. In addition, cultured neonatal rat atrial cardiomyocytes were stretched with the proposed device with different strain gradients. For the first time with this study we could demonstrate that stretch up to 21% caused dose-dependent changes in biological markers such as the calcineurin activity, modulatory calcineurin-interacting protein-1, voltage-gated potassium channel isoform 4.2, and voltage-gated K(+) channel-interacting proteins-2 gene expression and transient outward potassium current densities but not the protein-to-DNA ratio and atrial natriuretic peptide mRNA. With both markers mentioned last, dose-dependent stretch alterations could only be achieved with stretch up to 13%. The simple and low-cost device presented here might be applied to a wide range of experimental settings in different fields of research.

Increased functional importance of the Na,Ca-exchanger in contracting failing human myocardium but unchanged activity in isolated vesicles.

The present study aimed to investigate the hypothesis that the function of the Na,Ca-exchanger (NCX) is of higher importance for contractility and Ca(2+)-homeostasis in left ventricle from terminally failing than from nonfailing human hearts. The effect of decreasing extracellular [Na](e) (140 to 25 mmol/L) on force of contraction in isolated left ventricular papillary muscle strips was studied as a reflection of NCX function in multicellular preparations (terminally failing, DCM, dilated cardiomyopathy, NYHA IV, n = 13; nonfailing, NF, donor hearts, n = 10). Decreasing [Na](e) has previously been shown to increase contractility in vitro secondary to a decreased Ca(2+)-extrusion by the NCX. In addition, the NCX activity was measured as Na(+)-dependent (45)Ca(2+)-uptake into isolated myocardial vesicles as a function of time and Ca(2+)-concentration (DCM n = 8, NF n = 8). Decreasing [Na](e) enhanced the contractility of papillary muscle strips in both DCM and NF, but the contractility of DCM was increased at smaller reductions of [Na](e) than NF. The NCX activity in isolated myocardial vesicles was unchanged as a function of time (T(1/2): DCM 2.4 +/- 0.3 s versus NF 2.5 +/- 0.3 s) and as a function of Ca(2+) (DCM 0.99 +/- 0.08 versus NF 0.96 +/- 0.07 nmol/mg protein x 3 s, K(1/2): DCM 39.2 microM versus NF 38.3 microM). These results demonstrate a higher sensitivity of the failing human myocardium towards Na,Ca-exchanger mediated positive inotropic effects, suggesting a higher significance of the Na,Ca-exchanger for the extrusion of Ca(2+)-ions in intact failing versus nonfailing human myocardium. Since the activity and the Ca (2+)-affinity of the Na,Ca-exchanger in isolated vesicles was unchanged, we propose that alterations in Ca(2+)-and Na(+)-homeostasis (due to impaired function of the sarcoplasmic reticulum and the Na(+), K(+)-ATPase) or the prolonged action potential are the reason for this observation.

Losartan prevents stretch-induced electrical remodeling in cultured atrial neonatal myocytes.

Atrial fibrillation (AF) is the most frequent arrhythmia found in clinical practice. In recent studies, a decrease in the development or recurrence of AF was found in hypertensive patients treated with angiotensin-converting enzyme inhibitors or angiotensin receptor-blocking agents. Hypertension is related to an increased wall tension in the atria, resulting in increased stretch of the individual myocyte, which is one of the major stimuli for the remodeling process. In the present study, we used a model of cultured atrial neonatal rat cardiomyocytes under conditions of stretch to provide insight into the mechanisms of the preventive effect of the angiotensin receptor-blocking agent losartan against AF on a molecular level. Stretch significantly increased protein-to-DNA ratio and atrial natriuretic factor mRNA expression, indicating hypertrophy. Expression of genes encoding for the inward rectifier K(+) current (I(K1)), Kir 2.1, and Kir 2.3, as well as the gene encoding for the ultrarapid delayed rectifier K(+) current (I(Kur)), Kv 1.5, was significantly increased. In contrast, mRNA expression of Kv 4.2 was significantly reduced in stretched myocytes. Alterations of gene expression correlated with the corresponding current densities: I(K1) and I(Kur) densities were significantly increased in stretched myocytes, whereas transient outward K(+) current (I(to)) density was reduced. These alterations resulted in a significant abbreviation of the action potential duration. Losartan (1 microM) prevented stretch-induced increases in the protein-to-DNA ratio and atrial natriuretic peptide mRNA expression in stretched myocytes. Concomitantly, losartan attenuated stretch-induced alterations in I(K1), I(Kur), and I(to) density and gene expression. This prevented the stretch-induced abbreviation of action potential duration. Prevention of stretch-induced electrical remodeling might contribute to the clinical effects of losartan against AF.

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.

Altered tension cost in (TG(mREN-2)27) rats overexpressing the mouse renin gene.

The present study aimed to characterize cardiac hypertrophy induced by activation of the renin-angiotensin system in terms of functional alterations on the level of the contractile proteins, employing transgenic rats harboring the mouse renin gene (TGR(mREN2)27). Ca2+-dependent tension and myosin ATPase activity were measured in skinned fiber preparations obtained from TGR(mREN2)27 and from age-matched Sprague-Dawley rats (SPDR). Western blots for troponin I (TnI) and troponin T (TnT) were performed and the phosphorylation status of TnI were evaluated in myocardial preparations. TnT and myosin heavy chain (MHC) isoforms were analyzed by RT-PCR. The pCa/tension relationship was shifted to the right in TGR(mREN2)27 compared to SPDR as indicated by increased Ca2+-concentrations required for half maximal activation of tension (SPDR 5.80, 95% confidence limits 5.77-5.82 vs. TGR(mREN2)27 5.69, 95% confidence limits 5.67-5.72, pCa units), while maximal developed tension was unaltered. Even more pronounced was the shift in the relationship between pCa and myosin-ATPase (SPDR 6.01, 95% confidence limits 5.99-6.03 vs. TGR(mREN2)27 5.77, 95% confidence limits 5.73-5.79, pCa units). The maximal myosin-ATPase activity was reduced in TGR(mREN2)27 compared to SPDR, respectively (211.0 +/- 28.77 micromol ADP/s vs. 271.6 +/- 43.66 micromol ADP/s, P < 0.05). Tension cost (ATPase activity/tension) was significantly reduced in TGR(mREN2)27. The beta-MHC expression was significantly increased in TGR(mREN2)27. There was no isoform shift for TnT (protein and mRNA), as well as TnI, and no alteration of the phosphorylation of TnI in TGR(mREN2)27 compared to SPRD. The present study demonstrates that cardiac hypertrophy, induced by an activation of the renin-angiotensin system, leads to adapting alterations on the level of the contractile filaments, which reduce tension cost.