Electrotonic modulation of cardiac impulse conduction by myofibroblasts

Structural remodeling of the myocardium associated with mechanical overload or cardiac infarction is accompanied by the appearance of myofibroblasts. These fibroblast-like cells express alpha-smooth muscle actin (alphaSMA) and have been shown to express connexins in tissues other than heart. The present study examined whether myofibroblasts of cardiac origin establish heterocellular gap junctional coupling with cardiomyocytes and whether ensuing electrotonic interactions affect impulse propagation. For this purpose, impulse conduction characteristics (conduction velocity [theta] and maximal upstroke velocity [dV/dtmax]) were assessed optically in cultured strands of cardiomyocytes, which were coated with fibroblasts of cardiac origin. Immunocytochemistry showed that cultured fibroblasts underwent a phenotype switch to alphaSMA-positive myofibroblasts that expressed connexin 43 and 45 both among themselves and at contact sites with cardiomyocytes. Myofibroblasts affected theta and dV/dtmax in a cell density-dependent manner; a gradual increase of myofibroblast-to-cardiomyocyte ratios up to 7:100 caused an increase of both theta and dV/dtmax, which was followed by a progressive decline at higher ratios. On full coverage of the strands with myofibroblasts (ratio >20:100), theta fell <200 mm/s. This biphasic dependence of theta and dV/dtmax on myofibroblast density is reminiscent of "supernormal conduction" and is explained by a myofibroblast density-dependent gradual depolarization of the cardiomyocyte strands from -78 mV to -50 mV as measured using microelectrode recordings. These findings suggest that myofibroblasts, apart from their role in structural remodeling, might contribute to arrhythmogenesis by direct electrotonic modulation of conduction and that prevention of their appearance might represent an antiarrhythmic therapeutic target.

A novel steroid-like compound F90927 exerting positive-inotropic effects in cardiac muscle

Here we report a novel steroid-like compound F90363, exhibiting positive inotropy in vivo and in vitro in various cardiac muscle preparations. F90363 is a racemic mixture composed of the stereoisomers (-)-F90926 and (+)-F90927. Only F90927 exerted positive inotropy, while F90926 induced a weak negative inotropy, but only at concentrations 10(3) times higher than F90927 and most likely resulting from an unspecific interaction. The rapid time course of the action of F90927 suggested a direct interaction with a cellular target rather than a genomic alteration. We could identify the L-type Ca2+ current I(Ca(L)) as a main target of F90927, while excluding other components of cardiac Ca2+ signalling as potential contributors. In addition, several other signaling pathways known to lead to positive inotropy (e.g. alpha- and beta-adrenergic stimulation, cAMP pathways) could be excluded as targets of F90927. However, vessel contraction and stiffening of the cardiac muscle at high doses (>30 microM, 0.36 mg kg(-1), respectively) prevent the use of F90927 as a candidate for drug development. Since the compound may still find valuable applications in research, the aim of the present study was to identify the cellular target and the mechanism of inotropy of F90927.

Cardiac troponins as indicators of acute myocardial damage in dogs

Cardiac troponin I (cTnI) and T (cTnT) have a high sequence homology across phyla and are sensitive and specific markers of myocardial damage. The purpose of this study was to evaluate the Cardiac Reader, a human point-of-care system for the determination of cTnT and myoglobin, and the Abbott Axsym System for the determination of cTnI and creatine kinase isoenzyme MB (CK-MB) in healthy dogs and in dogs at risk for acute myocardial damage because of gastric dilatation-volvulus (GDV) and blunt chest trauma (BCT). In healthy dogs (n = 56), cTnI was below detection limits (<0.1 microg/L) in 35 of 56 dogs (reference range 0-0.7 microg/L), and cTnT was not measurable (<0.05 ng/mL) in all but 1 dog. At presentation, cTnI, CK-MB, myoglobin, and lactic acid were all significantly higher in dogs with GDV (n = 28) and BCT (n = 8) than in control dogs (P < .001), but cTnT was significantly higher only in dogs with BCT (P = .033). Increased cTnI or cTnT values were found in 26 of 28 (highest values 1.1-369 microg/L) and 16 of 28 dogs (0.1-1.7 ng/mL) with GDV, and in 6 of 8 (2.3-82.4 microg/L) and 3 of 8 dogs (0.1-0.29 ng/mL) with BCT, respectively. In dogs suffering from GDV, cTnI and cTnT increased further within the first 48 hours (P < .001). Increased cardiac troponins suggestive of myocardial damage occurred in 93% of dogs with GDV and 75% with BCT. cTnI appeared more sensitive, but cTnT may be a negative prognostic indicator in GDV. Both systems tested seemed applicable for the measurement of canine cardiac troponins, with the Cardiac Reader particularly suitable for use in emergency settings.

Electroporation-mediated interleukin-10 overexpression in skeletal muscle reduces acute rejection in rat cardiac allografts

OBJECTIVES: Human interleukin 10 (hIL-10) may reduce acute rejection after organ transplantation. Our previous data shows that electroporation-mediated transfer of plasmid DNA to peripheral muscle enhances gene transduction dramatically. This study was designed to investigate the effect of electroporation-mediated overexpression of hIL-10 on acute rejection of cardiac allografts in the rat. METHODS: The study was designed to evaluate the effect of hIL-10 gene transfer on (a) early rejection pattern and (b) graft survival. Gene transfer was achieved by intramuscular (i.m.) injection into the tibialis anterior muscle of Fischer (F344) male recipients followed by electroporation 24 h prior to transplantation. Heterotopic cardiac transplantation was performed from male Brown Norway rat to F344. Four groups were studied (n = 6). Treated animals in groups B1 and B2 received 2.5 microg of pCIK hIL-10 and control animals in groups A1 and A2 distilled water. Graft function was assessed by daily palpation. Animals from group A1 were sacrificed at the cessation of the heart beat of the graft and those in group B1 were sacrificed at day 7; blood was taken for ELISA measurement of hIL-10 and tissue for myeloperoxidase (MPO) measurement and histological assessment. To evaluate graft survival, groups A2 and B2 were sacrificed at cessation of the heart beat of the graft. RESULTS: Histological examination revealed severe rejection (IIIB-IV) in group A1 in contrast to low to moderate rejection (IA-IIIA) in group B1 (p = 0.02). MPO activity was significantly lower in group B1 compared to group A1 (18 +/- 7 vs. 32 +/- 14 mU/mg protein, p = 0.05). Serum hIL-10 levels were 46 +/- 13 pg/ml in group B1 vs. 0 pg/ml in group A1. At day 7 all heart allografts in the treated groups B1 and B2 were beating, whereas they stopped beating at 5 +/- 2 days in groups A1 and A2 vs. 14 +/- 2 days in group B2 (p = 0.0012). CONCLUSIONS: Electroporation-mediated intramuscular overexpression of hIL-10 reduces acute rejection and improves survival of heterotopic heart allografts in rats. This study demonstrates that peripheral overexpression of specific genes in skeletal muscle may reduce acute rejection after whole organ transplantation.

Diastolic dysfunction in human cardiac allografts is related with reduced SERCA2a gene expression

Previous studies demonstrated that impaired left ventricular (LV) relaxation in cardiac allografts limits exercise tolerance post-transplant despite preserved systolic ejection fraction (EF). This study tested in human cardiac allografts whether the isovolumic relaxation time (IVRT), which provides the basis for most of diastolic LV filling, relates with gene expression of regulatory proteins of calcium homeostasis or cardiac matrix proteins. Gene expression was studied in 31 heart transplant recipients (25 male, 6 female) 13-83 months post-transplant with LVEF >50%, LV end-diastolic pressure <20 mmHg, normal LV mass index and without allograft rejection or significant cardiac pathology. IVRT related with the other diastolic parameters e-wave velocity (r = -0.46; p = 0.01), e/a-wave ratio (r = -0.5; p < 0.01) but not with heart frequency (r = -0.16; p = 0.4). No relation of IVRT was observed for immunosuppression, mean rejection grade or other medication. IVRT was not related with gene expression of desmin, collagen I, phospholamban, the Na+-Ca2+ exchanger, the ryanodine receptor or interstitial fibrosis but correlated inversely with SERCA2a (r = -0.48; p = 0.02). Prolonged IVRT is associated with decreased SERCA2a expression in cardiac allografts without significant other pathology. Similar observations in non-transplanted patients with diastolic failure suggest that decreased SERCA2a expression is an important common pathomechanism.

Influence of water immersion, water gymnastics and swimming on cardiac output in patients with heart failure

Background Whole-body water immersion leads to a significant shift of blood from the periphery into the intra-thoracic circulation, followed by an increase in central venous pressure and heart volume. In patients with severely reduced left ventricular function, this hydrostatically in-duced volume shift might overstrain the cardiovascular adaptive mechanisms and lead to cardiac decompensation. The aim of this study is to assess the hemodynamic response to water immer-sion, gymnastics and swimming in patients with heart failure (CHF). Methods We examined 10 patients with compensated CHF (62.9 +/- 6.3 years, EF 31.5 +/- 4.1%, peak VO2 19.4 +/- 2.8 ml/kg/min.), 10 patients with coronary artery disease (CAD) but preserved left ventricular function (57.2 +/- 5.6 years, EF 63.9 +/- 5.5%, peak VO2 28.0 +/- 6.3 ml/kg/min.) and 10 healthy subjects (32.8 +/- 7.2 years, peak VO2 45.6 +/- 6.0 ml/kg/min.). Hemodynamic response to thermo-neutral (32 degrees C) water immersion and exercise was measured using a non-invasive foreign gas rebreathing method during stepwise water immersion, water gymnastics and swimming. Results Water immersion up to the chest increased cardiac index by 19% in healthy subjects, by 21% in CAD patients and 16% in CHF patients. While some CHF patients showed a decrease of stroke volume during immersion, all subjects were able to increase cardiac index (by 87% in healthy subjects, 77% in CAD patients and 53% in CHF patients). Oxygen uptake during swim-ming was 9.7 +/- 3.3 ml/kg/min. in CHF patients, 12.4 +/- 3.5 ml/kg/min. in CAD patients and 13.9 +/- 4.0 ml/kg/min. in healthy subjects. Conclusions Patients with severely reduced left ventricular function but stable clinical conditions and a minimal peak VO2 of at least 15 ml/kg/min. during a symptom-limited exercise stress test tolerate water immersion and swimming in thermo-neutral water well. Although cardiac in-dex and oxygen uptake are lower compared with CAD patients with preserved left ventricular function and healthy controls, these patients are able to increase cardiac index adequately during water immersion and swimming.

Giant coronary artery fistula complicated by cardiac tamponade

A 30 year old female was admitted to the hospital with cardiogenic shock due to cardiac tamponade. A ruptured giant coronary artery fistula (CAF) originating from the left main coronary artery draining into the right atrium was identified as the cause. In this case report we describe the clinical course with emphasis on diagnostic work-up and imaging.

Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) belongs to the TNF family known to transduce their death signals via cell membrane receptors. Because it has been shown that Apo2L/TRAIL induces apoptosis in tumor cells without or little toxicity to normal cells, this cytokine became of special interest for cancer research. Unfortunately, cancer cells are often resistant to Apo2L/TRAIL-induced apoptosis; however, this can be at least partially negotiated by parallel treatment with other substances, such as chemotherapeutic agents. Here, we report that cardiac glycosides, which have been used for the treatment of cardiac failure for many years, sensitize lung cancer cells but not normal human peripheral blood mononuclear cells to Apo2L/TRAIL-induced apoptosis. Sensitization to Apo2L/TRAIL mediated by cardiac glycosides was accompanied by up-regulation of death receptors 4 (DR4) and 5 (DR5) on both RNA and protein levels. The use of small interfering RNA revealed that up-regulation of death receptors is essential for the demonstrated augmentation of apoptosis. Blocking of up-regulation of DR4 and DR5 alone significantly reduced cell death after combined treatment with cardiac glycosides and Apo2L/TRAIL. Combined silencing of DR4 and DR5 abrogated the ability of cardiac glycosides and Apo2L/TRAIL to induce apoptosis in an additive manner. To our knowledge, this is the first demonstration that glycosides up-regulate DR4 and DR5, thereby reverting the resistance of lung cancer cells to Apo2/TRAIL-induced apoptosis. Our data suggest that the combination of Apo2L/TRAIL and cardiac glycosides may be a new interesting anticancer treatment strategy.

Important excess morbidity due to upper airway anomalies in the perioperative course in infant cardiac surgery

BACKGROUND: The study aimed at defining the excess morbidity or mortality caused by an additional airway malformation in children with congenital heart disease requiring surgery. METHODS: All patients requiring surgery for heart disease during an 8-year period ending in 2003 who had an associated upper airway malformation were retrospectively studied. All patients were seen in 2004 for a prospective follow-up examination. RESULTS: Eleven patients with upper airway anomalies were identified (tracheobronchial malacia in 6 patients, long-segment tracheal stenosis in 3, and bilateral vocal cord paralysis and tracheal hemangioma in 1 patient each). They accounted for 1.5% of the entire cardiac surgical load of 764 patients. In 5 infants, the airway anomaly was diagnosed before cardiac repair, in 6 patients thereafter. Diagnosis was made by bronchoscopy in all patients, by additional bronchography in 2. Failure of rapid postoperative extubation was the most common finding. Airway management was surgical in 2 and conservative in 8 patients, 1 newborn having been denied therapy because of the severity of airway hypoplasia. Compared with patients with isolated cardiac disease, those with additional airway anomalies had significantly longer duration of postoperative mechanical ventilation (median, 24 days versus 3), perioperative hospitalization (median, 72 days versus 11) and total number of days of hospitalization during the first year of life (median, 104 days versus 14). After a maximum follow-up of 8 years (median, 37 months) only 3 of 10 surviving patients remained symptomatic owing to the airway malformation. CONCLUSIONS: Upper airway anomalies accompanying heart disease in infancy resulted in a significant prolongation of perioperative intensive care and hospital stay, as well as duration of mechanical ventilation. Failure of early postoperative extubation was the leading symptom.

Arterio-venous gradients of free energy change for assessment of systemic and splanchnic perfusion in cardiac surgery patients

OBJECTIVE: Adequacy of organ perfusion depends on sufficient oxygen supply in relation to the metabolic needs. The aim of this study was to evaluate the relationship between gradients of free energy change, and the more commonly used parameter for the evaluation of the adequacy of organ perfusion, such as oxygen-extraction in patients undergoing valve replacement surgery using normothermic cardiopulmonary bypass (CPB). METHODS: In 43 cardiac patients, arterial, mixed venous, and hepato-venous blood samples were taken synchronously after induction of anaesthesia (preCPB), during CPB, and 2 and 7 h after admission to the intensive care unit (ICU+2, ICU+7). Blood gas analysis, cardiac output, and hepato-splanchnic blood flow were measured. Free energy change gradients between mixed venous and arterial (-deltadeltaG(v - a)) and hepato-venous and arterial (-deltadeltaG(hv - a)) compartments were calculated. MEASUREMENTS AND RESULTS: Cardiac index (CI) increased from 1.9 (0.7) to 2.8 (1.3) L/min/m (median, inter-quartile range) (p = 0.001), and hepato-splanchnic blood flow index (HBFI) from 0.6 (0.22) to 0.8 (0.53) L/min/m (p = 0.001). Despite increasing flow, systemic oxygen extraction increased after CPB from 24 (10)% to 35 (10)% at ICU+2 (p = 0.002), and splanchnic oxygen extraction increased during CPB from 37 (19)% to 52 (14)% (p = 0.001), and remained high thereafter. After CPB, high splanchnic and systemic gradients of free energy change gradients were associated with high splanchnic and systemic oxygen extraction, respectively (p = 0.001, 0.033, respectively). CONCLUSION: Gradients of free energy change may be helpful in characterising adequacy of perfusion in cardiac surgery patients independently from measurements or calculations of data from oxygen transport.

Are there accurate predictors of long-term vital and functional outcomes in cardiac surgical patients requiring prolonged intensive care?

BACKGROUND AND OBJECTIVE: The decision to maintain intensive treatment in cardiac surgical patients with poor initial outcome is mostly based on individual experience. The risk scoring systems used in cardiac surgery have no prognostic value for individuals. This study aims to assess (a) factors possibly related to poor survival and functional outcomes in cardiac surgery patients requiring prolonged (> or = 5 days) intensive care unit (ICU) treatment, (b) conditions in which treatment withdrawal might be justified, and (c) the patient's perception of the benefits and drawbacks of long intensive treatments. METHODS: The computerized data prospectively recorded for every patient in the intensive care unit over a 3-year period were reviewed and analyzed (n=1859). Survival and quality of life (QOL) outcomes were determined in all patients having required > or =5 consecutive days of intensive treatment (n=194/10.4%). Long-term survivors were interviewed at yearly intervals in a standardized manner and quality of life was assessed using the dependency score of Karnofsky. No interventions or treatments were given, withhold, or withdrawn as part of this study. RESULTS: In-hospital, 1-, and 3-year cumulative survival rates reached 91.3%, 85.6%, and 75.1%, respectively. Quality of life assessed 1 year postoperatively by the score of Karnofsky was good in 119/165 patients, fair in 32 and poor in 14. Multivariate logistic regression analysis of 19 potential predictors of poor outcome identified dialysis as the sole factor significantly (p=0.027) - albeit moderately - reducing long-term survival, and sustained neurological deficit as an inconstant predictor of poor functional outcome (p=0.028). One year postoperatively 0.63% of patients still reminded of severe suffering in the intensive station and 20% of discomfort. Only 7.7% of patients would definitely refuse redo surgery. CONCLUSIONS: This study of cardiac surgical patients requiring > or =5 days of intensive treatment did not identify factors unequivocally justifying early treatment limitation in individuals. It found that 1-year mortality and disability rates can be maintained at a low level in this subset of patients, and that severe suffering in the ICU is infrequent.

The 2002 European registry of cardiac catheter interventions

OBJECTIVE: The tradition of yearly reports on cardiac catheter interventions in Europe has been initiated in 1992. This 11th report presents aggregated data on cardiac catheter procedures in 30 European countries in the year 2002. DESIGN AND SETTING: A detailed questionnaire addressing summary data of all cardiac interventions was mailed to presidents or delegates of the national societies of cardiology in Europe. The questionnaire was distributed to all institutions with cardiac catheterisation programs. All questionnaires were compiled in a national summary data sheet, then entered into a central database and subsequently analysed. MAIN OUTCOME MEASURES: Coronary angiography, PTCA, and stenting in absolute numbers and per million inhabitants in the participating countries and the whole of Europe. RESULTS: Overall, 1,901,932 coronary angiograms were reported. The population-adjusted rate of coronary angiograms amounted to an absolute mean of 3358 per 10(6) inhabitants, an increase of 7% compared with 2001. A total of 686,869 PTCA procedures were reported. The mean European number of PTCAs per 10(6) inhabitants increased by 10% from 1103 in 2001 to 1213 in 2002. Procedures with stenting increased by 17% from 508,999 to 593,906. The stenting rate was 86% compared with 82% in 2001. CONCLUSIONS: In pace with epidemiological demand and the need to catch-up from underuse in certain countries, a continuous and considerable growth of coronary interventions can be observed. It will take years to find out whether the announced change of paradigm in the treatment of multivessel disease in the wake of drug-eluting stents will come true.