[Stem cell transfer after myocardial infarction--Against].
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Evidence-Based Medicine↗
Biomedical subjects
N Frey
Publications and source records attributed to N Frey.
Rapid progressive eosinophilic cardiomyopathy in a patient with Churg-Strauss syndrome (CSS).
Churg-Strauss syndrome (CSS) is a rare necrotizing, systemic vasculitis that is almost invariably associated with bronchial asthma. Although overall prognosis is good and treatment with corticosteroids alone or in combination with other immunosuppressive agents is typically successful, there are reports of patients that do not show signs of clinical improvement under the usual pharmacotherapy. Small clinical studies suggested that cardiac or gastrointestinal involvement is associated with an adverse prognosis. We here report the case of a 38 year old male patient with a history of bronchial asthma who was admitted to our hospital for further evaluation of progressive dyspnea. Blood eosinophilia, infiltrates of both lungs, signs of necrosis and eosinophil deposits on myocardial biopsy combined with a history of bronchial asthma established the diagnosis of CSS with cardiac involvement. We initiated an immunosuppressive therapy with prednisone and methotrexate. Upon tapering of the dosage of prednisone, we noticed worsening of symptoms and further deterioration of cardiac function. Despite the addition of cyclophosphamide and adjustment of heart failure medication, we were not able to stabilize the cardiac situation. Due to rapid progressive eosinophilic cardiomyopathy associated with CSS refractory to medical therapy, our patient was placed on the urgent heart transplantation waiting list and, in the meantime, has undergone successful cardiac transplantation.
Adult↗
Cardiac hypertrophy: the good, the bad, and the ugly.
Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress. While hypertrophy can eventually normalize wall tension, it is associated with an unfavorable outcome and threatens affected patients with sudden death or progression to overt heart failure. Accumulating evidence from studies in human patients and animal models suggests that in most instances hypertrophy is not a compensatory response to the change in mechanical load, but rather is a maladaptive process. Accordingly, modulation of myocardial growth without adversely affecting contractile function is increasingly recognized as a potentially auspicious approach in the prevention and treatment of heart failure. In this review, we summarize recent insights into hypertrophic signaling and consider several novel antihypertrophic strategies.
Adaptation, Physiological↗
Population PKPD modelling of the long-term hypoglycaemic effect of gliclazide given as a once-a-day modified release (MR) formulation.
AIMS: To study the relationship between the pharmacokinetics (PK) of gliclazide and its long-term pharmacodynamic (PD) effect in a large population of Type 2 diabetic patients and to identify factors predicting intersubject variability. METHODS: A PKPD database of 634 Type 2 diabetic patients with a total of 5,258 fasting plasma glucose (FPG) samples was built up from the data collected during the clinical development of a modified release formulation of gliclazide (gliclazide MR). The PKPD analysis used a nonlinear mixed effect modelling approach. A mixture model was used to identify patients with a FPG response to treatment. In patients identified as responders, the decrease in FPG was related to gliclazide exposure (AUC) by an Emax relationship. An effect compartment was used to describe the link between PK and PD. A linear disease-progression model was used to assess the glycaemic deterioration observable over several months of treatment. Simulations were performed to evaluate the predictive performance of the PKPD model and to illustrate the time course of the antidiabetic effect of gliclazide MR. RESULTS: Disease state was found to be the main explanatory factor for intersubject variability in response to gliclazide. The percentage of responders to gliclazide, used as monotherapy, increased inversely to the number of classes of antidiabetic agents received prior to entry in the studies. In responders, the initial dose (30 mg) of the gliclazide MR dosing regimen induced half of the maximum hypoglycaemic effect. The equilibration half-life between the PK and PD steady states was 3 weeks (intersubject variability of 84%). The rate of disease progression was 0.84 mmol l(-1) year(-1) (intersubject variability 143%). The PKPD model adequately predicted the FPG profiles of 234 patients who received the current formulation of gliclazide. Simulation of a 1-year parallel dose ranging clinical trial illustrated the influence of dose, time and type of previous antidiabetic treatment on the percentage of patients with clinically significant improvement of blood glucose control. CONCLUSIONS: This population PKPD analysis has characterized the relationship between the exposure to gliclazide and its long-term hypoglycaemic effect, and has established that the intersubject variability in response is mostly related to disease state. These results underline the clinical interest of quickly increasing the dose of gliclazide MR according to the response to treatment in order to achieve effective blood glucose control.
Blood Glucose↗
Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase a.
beta-Adrenergic receptor (betaAR) signaling, which elevates intracellular cAMP and enhances cardiac contractility, is severely impaired in the failing heart. Protein kinase A (PKA) is activated by cAMP, but the long-term physiological effect of PKA activation on cardiac function is unclear. To investigate the consequences of chronic cardiac PKA activation in the absence of upstream events associated with betaAR signaling, we generated transgenic mice that expressed the catalytic subunit of PKA in the heart. These mice developed dilated cardiomyopathy with reduced cardiac contractility, arrhythmias, and susceptibility to sudden death. As seen in human heart failure, these abnormalities correlated with PKA-mediated hyperphosphorylation of the cardiac ryanodine receptor/Ca(2+)-release channel, which enhances Ca(2+) release from the sarcoplasmic reticulum, and phospholamban, which regulates the sarcoplasmic reticulum Ca(2+)-ATPase. These findings demonstrate a specific role for PKA in the pathogenesis of heart failure, independent of more proximal events in betaAR signaling, and support the notion that PKA activity is involved in the adverse effects of chronic betaAR signaling.
Animals↗
Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy.
Mitogen-activated protein kinase (MAPK) pathways couple intrinsic and extrinsic signals to hypertrophic growth of cardiomyocytes. The MAPK kinase MEK5 activates the MAPK ERK5. To investigate the potential involvement of MEK5-ERK5 in cardiac hypertrophy, we expressed constitutively active and dominant-negative forms of MEK5 in cardiomyocytes in vitro. MEK5 induced a form of hypertrophy in which cardiomyocytes acquired an elongated morphology and sarcomeres were assembled in a serial manner. The cytokine leukemia inhibitory factor (LIF), which stimulates MEK5 activity, evoked a similar response. Moreover, a dominant-negative MEK5 mutant specifically blocked LIF-induced elongation of cardiomyocytes and reduced expression of fetal cardiac genes without blocking other aspects of LIF-induced hypertrophy. Consistent with the ability of MEK5 to induce serial assembly of sarcomeres in vitro, cardiac-specific expression of activated MEK5 in transgenic mice resulted in eccentric cardiac hypertrophy that progressed to dilated cardiomyopathy and sudden death. These findings reveal a specific role for MEK5-ERK5 in the induction of eccentric cardiac hypertrophy and in transduction of cytokine signals that regulate serial sarcomere assembly.
Animals↗
Angiographic correlates of a positive troponin T test in patients with unstable angina.
OBJECTIVE: To study the angiographic correlates of cardiac troponin T (cTnT)-positive and -negative patients with unstable angina pectoris. BACKGROUND: A positive cTnT test identifies a high-risk subgroup of unstable angina pectoris patients. Only the high-risk cTnT-positive patients seem to benefit from a more aggressive antithrombotic treatment regimen. The underlying coronary pathology in cTnT-positive and -negative patients that explains the predictive power of cTnT on prognosis and response to antithrombotic therapy is largely unknown. METHODS: A total of 197 subsequently admitted patients with unstable angina pectoris underwent cTnT testing by a rapid bedside assay and early qualitative and quantitative angiography. Long-term follow-up was 12 months. RESULTS: Patients with cTnT-positive tests revealed more critical stenoses of culprit lesions (p =.041), more severe reductions of thrombolysis in myocardial infarction flow grades (p <.037), a higher prevalence of intracoronary thrombus (p =.079), and a poorer left ventricular function (p =.047). The odds ratio of cTnT was 5.8 (p <.0001) for presence of thrombus, reduced thrombolysis in myocardial infarction flow, and/or critical stenosis (>90%), and was 3.1 (p =.005) for presence of three-vessel disease, left main disease, and/or reduced left ventricular ejection fraction. Coronary bypass grafting was more frequently performed in the cTnT-positive group. However, event-free survival was not different in our cohort characterized by a high rate of percutaneous coronary interventions. CONCLUSIONS: A positive cTnT test in patients with unstable angina pectoris indicates presence of more severe coronary artery disease and poorer left ventricular function. This finding could explain the differences in short- and long-term outcome and treatment responses to antithrombotic regimens.
Aged↗
Calsarcins, a novel family of sarcomeric calcineurin-binding proteins.
The calcium- and calmodulin-dependent protein phosphatase calcineurin has been implicated in the transduction of signals that control the hypertrophy of cardiac muscle and slow fiber gene expression in skeletal muscle. To identify proteins that mediate the effects of calcineurin on striated muscles, we used the calcineurin catalytic subunit in a two-hybrid screen for cardiac calcineurin-interacting proteins. From this screen, we discovered a member of a novel family of calcineurin-interacting proteins, termed calsarcins, which tether calcineurin to alpha-actinin at the z-line of the sarcomere of cardiac and skeletal muscle cells. Calsarcin-1 and calsarcin-2 are expressed in developing cardiac and skeletal muscle during embryogenesis, but calsarcin-1 is expressed specifically in adult cardiac and slow-twitch skeletal muscle, whereas calsarcin-2 is restricted to fast skeletal muscle. Calsarcins represent a novel family of sarcomeric proteins that link calcineurin with the contractile apparatus, thereby potentially coupling muscle activity to calcineurin activation.
Actinin↗
Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles.
Calcineurin, a calcium/calmodulin-regulated protein phosphatase, modulates gene expression in cardiac and skeletal muscles during development and in remodeling responses such as cardiac hypertrophy that are evoked by environmental stresses or disease. Recently, we identified two genes encoding proteins (MCIP1 and MCIP2) that are enriched in striated muscles and that interact with calcineurin to inhibit its enzymatic activity. In the present study, we show that expression of MCIP1 is regulated by calcineurin activity in hearts of mice with cardiac hypertrophy, as well as in cultured skeletal myotubes. In contrast, expression of MCIP2 in the heart is not altered by activated calcineurin but responds to thyroid hormone, which has no effect on MCIP1. A approximately 900-bp intragenic segment located between exons 3 and 4 of the MCIP1 gene functions as an alternative promoter that responds to calcineurin. This region includes a dense cluster of 15 consensus binding sites for NF-AT transcription factors. Because MCIP proteins can inhibit calcineurin, these results suggest that MCIP1 participates in a negative feedback circuit to diminish potentially deleterious effects of unrestrained calcineurin activity in cardiac and skeletal myocytes. Inhibitory effects of MCIP2 on calcineurin activity may be pertinent to gene switching events driven by thyroid hormone in striated muscles. The full text of this article is available at http://www. circresaha.org.
Animals↗
Transgenic rat hearts expressing a human cardiac troponin T deletion reveal diastolic dysfunction and ventricular arrhythmias.
OBJECTIVE: Familial hypertrophic cardiomyopathy (FHC) due to mutations of cardiac troponin T (cTnT) is associated with a high frequency of sudden death even in the absence of cardiac hypertrophy. To investigate the causal relationship of cTnT mutations and this particular phenotype, we sought to establish a transgenic rat model for the disease. METHODS: Transgenic rats were generated expressing human wild-type cTnT or two truncated cTnT molecules (del ex16, del ex15/16), resulting from an intron 15 splice donor site mutation previously observed in FHC patients. Transgenic rat hearts were characterized by histology, immunohistochemistry and in the 'working heart'. RESULTS: Human wild-type and del ex16 cTnT were stably expressed and incorporated into the sarcomere of transgenic cardiomyocytes. Del ex16 transgenic rats revealed a lower level of expression (4-5%) than human wt cTnT animals (25-40%). In the 'working heart' model del ex16 hearts exhibited significant systolic and diastolic dysfunction without cardiac hypertrophy. In contrast, human wt cTnT hearts showed improved contractile performance and moderate myocardial hypertrophy. After 6 months of daily physical exercise one del ex16 rat died suddenly and three out of five del ex16 hearts revealed ventricular tachycardia/fibrillation. No arrhythmia was observed in human wt cTnT expressors. Myofibrillar disarray was present in del ex16 hearts after training but not in human wild-type cTnT rats or non-transgenic controls. CONCLUSION: A human cTnT deletion overexpressed in transgenic rats exerts a dominant-negative effect and mimics the phenotype of FHC with diastolic dysfunction and arrhythmias. By contrast, human cTnT wild-type animals reveal a gain of function and cardiac hypertrophy without arrhythmias.
Animals↗
Decoding calcium signals involved in cardiac growth and function.
Calcium is central in the regulation of cardiac contractility, growth and gene expression. Variations in the amplitude, frequency and compartmentalization of calcium signals are decoded by calcium/calmodulin-dependent enzymes, ion channels and transcription factors. Understanding the circuitry for calcium signaling creates opportunities for pharmacological modification of cardiac function.
Animals↗
From the sarcomere to the nucleus: role of genetics and signaling in structural heart disease.
The identification of genetic mutations underlying familial structural heart disease has provided exciting new insights into how alterations in structural components of the cardiomyocyte lead to different forms of cardiomyopathy. Specifically, mutations in components of the sarcomere are frequently associated with hypertrophic cardiomyopathy, whereas mutations in cytoskeletal proteins lead to dilated cardiomyopathy. In addition, extrinsic stresses such as hypertension and valvular disease can produce myocardial remodeling that is very similar to that observed in genetic cardiomyopathy. For myocardial remodeling to occur, changes in gene expression must occur; therefore, changes in contractile function or wall stress must be communicated to the nucleus via signal transduction pathways. The identity of these signaling pathways has become a key question in molecular biology. Numerous signaling molecules have been implicated in the development of hypertrophy and failure, including the beta-adrenergic receptor, G alpha(q) and downstream effectors, mitogen-activated protein kinase pathways, and the Ca(2+)-regulated phosphatase, calcineurin. In the past it has been difficult to discern which signaling molecules actually contributed to disease progression in vivo; however, the development of numerous transgenic and knockout mouse models of cardiomyopathy is now allowing the direct testing of stimulatory and inhibitory molecules in the mouse heart. From this work it has been possible to identify signaling molecules and pathways that are required for different aspects of disease progression in vivo. In particular, a number of signaling pathways have now been identified that may be key regulators of changes in myocardial structure and function in response to mutations in structural components of the cardiomyocyte. Myocardial structure and signal transduction are now merging into a common field of research that will lead to a more complete understanding of the molecular mechanisms that underly heart disease.
Animals↗
Making matters worse for a broken heart.
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Animals↗
CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo.
Hypertrophic growth is an adaptive response of the heart to diverse pathological stimuli and is characterized by cardiomyocyte enlargement, sarcomere assembly, and activation of a fetal program of cardiac gene expression. A variety of Ca(2+)-dependent signal transduction pathways have been implicated in cardiac hypertrophy, but whether these pathways are independent or interdependent and whether there is specificity among them are unclear. Previously, we showed that activation of the Ca(2+)/calmodulin-dependent protein phosphatase calcineurin or its target transcription factor NFAT3 was sufficient to evoke myocardial hypertrophy in vivo. Here, we show that activated Ca(2+)/calmodulin-dependent protein kinases-I and -IV (CaMKI and CaMKIV) also induce hypertrophic responses in cardiomyocytes in vitro and that CaMKIV overexpressing mice develop cardiac hypertrophy with increased left ventricular end-diastolic diameter and decreased fractional shortening. Crossing this transgenic line with mice expressing a constitutively activated form of NFAT3 revealed synergy between these signaling pathways. We further show that CaMKIV activates the transcription factor MEF2 through a posttranslational mechanism in the hypertrophic heart in vivo. Activated calcineurin is a less efficient activator of MEF2-dependent transcription, suggesting that the calcineurin/NFAT and CaMK/MEF2 pathways act in parallel. These findings identify MEF2 as a downstream target for CaMK signaling in the hypertrophic heart and suggest that the CaMK and calcineurin pathways preferentially target different transcription factors to induce cardiac hypertrophy.
Animals↗
The 2.3 kb smooth muscle myosin heavy chain promoter directs gene expression into the vascular system of transgenic mice and rabbits.
BACKGROUND: Smooth muscle cells (SMC) are a preferential target for gene therapeutic approaches in atherosclerosis and restenosis. However, the undesirable expression of putative therapeutic genes in tissues other than the vascular wall is a considerable safety limitation for clinical trials, thus requiring the identification of a smooth-muscle-specific promoter sequence. Since the 2.3 kb rabbit Smooth Muscle Myosin Heavy Chain (SMHC) promoter was shown to be transcriptionally active in primary vascular but not visceral or other non-SMC in vitro, this fragment was chosen for in vivo analysis. METHODS AND RESULTS: Transgenic mice and rabbits were established expressing a luciferase reporter gene under control of the 2.3 kb rabbit SMHC promoter. In contrast to the endogenous expression pattern of the SMHC gene both species revealed light emission predominantly in the arterial system including coronary arteries. Low activities were measured in large veins and the gastrointestinal system. In situ hybridization of murine embryos using a luciferase riboprobe confirmed reporter gene expression in large arteries with no detectable mRNA in the viscera. Unlike adult animals, ectopic luciferase activities were found in ventricular myocardium during murine development ceasing 1 week post partum. CONCLUSIONS: In two animal species, the 2.3 kb SMHC promoter appeared to be effective in discriminating between the pathways regulating vascular and visceral smooth muscle gene expression. The vascular-specific expression profile of the 2.3 kb SMHC promoter suggests that the 2.3 kb SMHC promoter contains the regulatory elements necessary for selective gene targeting into vascular SMC of large arteries including coronary arteries in vivo.
Animals↗
Cardiac troponins in patients with chest pain.
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Biomarkers↗
[Value of laboratory parameters in risk assessment of patients with coronary heart disease and chronic myocardial ischemia].
The main purpose of laboratory tests in patients with acute coronary syndromes is the exclusion of an acute myocardial infarction and the detection of myocardial micronecrosis. Patients with minor myocardial cell damage can best be identified by measurement of cardiac troponin T and possibly also cardiac troponin I levels. Other serum markers of acute ischemia lack specificity and are, therefore, currently of little clinical significance.
Blood Chemical Analysis↗
Biochemical markers in the diagnosis of coronary artery disease.
For many years cardiac markers have been used to classify whether chest pain is attributable to acute myocardial infarction or not. However massive, myocardial infarction is frequently preceded by plaque inflammation and local thrombus formation. Novel cardiac markers focus on detection of these more subtle manifestations of coronary artery disease. Detection of inflammation of coronary artery plaques is best achieved by measurement of C-reactive protein and fibrinogen, while thrombus formation may be assessed by testing for fibrin formation and platelet activation. When coronary flow is severely impaired minor myocardial injury will occur and cellular constituents may egress from damaged myocytes. Among the many cardiac markers for myocardial cell necrosis, troponin T revealed the highest sensitivity and cardio-specificity. The superior performance of troponin T has not only refined detection of myocardial cell necrosis but has also improved the risk stratification process and may even facilitate therapeutic decision making in patients with acute coronary syndrome. This review will summarize the characteristics and performance of diagnostic tools used for classification and risk stratification of patients with suspected myocardial injury.
Biomarkers↗