Karl Mischke

Augmentation of Left Ventricular Contractility by Cardiac Sympathetic Neural Stimulation

Background— Electric stimulation of mediastinal sympathetic cardiac nerves increases cardiac contractility but is not selective for the left ventricle because it elicits sinus tachycardia and enhanced atrioventricular conduction. The aim of this study was to identify sympathetic neural structures inside the heart that selectively control left ventricular inotropy and can be accessed by transvenous catheter stimulation. Methods and Results— In 20 sheep, high-frequency stimulation (200 Hz) during the myocardial refractory period with electrode catheters inside the coronary sinus evoked a systolic left ventricular pressure increase from 97±20 to 138±32 mm Hg (P<0.001) without changes in sinus rate or PR time. Likewise, the rate of systolic pressure development (1143±334 versus 1725±632 mm Hg/s; P=0.004) and rate of diastolic relaxation (531±128 versus 888±331 mm Hg/s; P=0.001) increased. The slope of the end-systolic pressure-volume relationship increased (2.3±0.8 versus 3.1±0.6 mm Hg/mL; P=0.04), as did cardiac output (3.5±0.8 versus 4.4±0.8 L/min; P<0.001). Systemic vascular resistance and right ventricular pressure remained unchanged. There was a sigmoid dose-response curve. Ultrasound analysis revealed an increase in circumferential and radial strain in all left ventricular segments that was significant for the posterior, lateral, and anterior segments. Pressure effects were maintained for at least 4 hours of continued high-frequency stimulation and abolished by &bgr;1-receptor blockade. Histology showed distinct adrenergic nerve bundles at the high-frequency stimulation site. Conclusions— Cardiac nerve fibers that innervate the left ventricle are amenable to transvenous electric catheter stimulation. This may permit direct interference with and modulation of the sympathetic tone of the left ventricle.

Regulation of nerve growth factor in the heart: the role of the calcineurin-NFAT pathway.

A heightened sympathetic tone accelerates the development of lethal arrhythmias after myocardial infarction (MI) and the progression of heart failure (HF). Cardiomyocytes control their local neural milieu by expression of nerve growth factor (NGF), which triggers sympathetic neural growth (sympathetic nerve sprouting: SNS). The molecular mechanisms that regulate NGF expression are largely unknown. During HF or MI the myocytes are exposed to increased mechanical load and adrenergic stimulation. Both stimuli induce myocyte hypertrophy. The angiotensin-II-calcineurin-NFAT (nuclear factor of activated t-cells) pathway is a well characterized signaling cascade in the pathogenesis of myocyte hypertrophy. The present study aims to investigate the molecular mechanisms by which mechanical stretch and/or alpha-1-adrenergic stimulation affect NGF expression in neonatal rat ventricular myocytes. Both stimuli resulted in a down-regulation of NGF gene and protein expression. Angiotensin-II type 1 receptor blockade with losartan blunted the stretch-induced NGF down-regulation. Specific calcineurin inhibition with cyclosporine A and FK506 or NFAT inhibition with 11R-VIVIT reversed the stretch or alpha-1-adrenergic induced decrease of NGF. Calcineurin over-expression increased NFAT-DNA binding activity and decreased NGF expression. The magnitude of NGF decrease was sufficient to reduce neurite outgrowth of cultured sympathetic neurons. In conclusion, mechanical stretch and alpha-1-adrenergic stimulation contribute to a decrease of cardiomyocyte NGF expression via the calcineurin-NFAT pathway. To evaluate if the calcineurin-NFAT is critically involved in the pathogenesis of SNS further in-vivo studies in models of HF and MI are required. Nevertheless, the calcineurin-NFAT pathway may provide promising starting points for new pharmacological strategies to prevent SNS in the heart.

Epicardial neural ganglionated plexus of ovine heart: Anatomic basis for experimental cardiac electrophysiology and nerve protective cardiac surgery

BACKGROUND Sheep are routinely used in experimental cardiac electrophysiology and surgery. OBJECTIVE The purpose of this study was to (1) ascertain the topography and architecture of the ovine epicardial neural plexus (ENP), (2) determine the relationships of ENP with vagal and sympathetic cardiac nerves and ganglia, and (3) evaluate gross anatomic differences and similarities of ENP in humans, sheep, and other species. METHODS Ovine ENP and extrinsic sympathetic and vagal nerves were stained histochemically for acetylcholinesterase in whole heart and/or thorax-dissected preparations from 23 newborn lambs, with subsequent examination by stereomicroscope. RESULTS Intrinsic cardiac nerves extend from the venous part of the ovine heart hilum along the roots of the cranial (superior) caval and left azygos veins to both atria and ventricles via five epicardial routes: dorsal right atrial, middle dorsal, left dorsal, right ventral, and ventral left atrial nerve subplexuses. Intrinsic nerves proceeding from the arterial part of the heart hilum along the roots of the aorta and pulmonary trunk extend exclusively into the ventricles as the right and left coronary subplexuses. The dorsal right atrial, right ventral, and middle dorsal subplexuses receive the main extrinsic neural input from the right cervicothoracic and right thoracic sympathetic T(2) and T(3) ganglia as well as from the right vagal nerve. The left dorsal is supplied by sizeable extrinsic nerves from the left thoracic T(4)-T(6) sympathetic ganglia and the left vagal nerve. Sheep hearts contained an average of 769 +/- 52 epicardial ganglia. Cumulative areas of epicardial ganglia on the root of the cranial vena cava and on the wall of the coronary sinus were the largest of all regions (P <.05). CONCLUSION Despite substantial interindividual variability in the morphology of ovine ENP, right-sided epicardial neural subplexuses supplying the sinoatrial and atrioventricular nodes are mostly concentrated at a fat pad between the right pulmonary veins and the cranial vena cava. This finding is in sharp contrast with a solely left lateral neural input to the human atrioventricular node, which extends mainly from the left dorsal and middle dorsal subplexuses. The abundance of epicardial ganglia distributed widely along the ovine ventricular nerves over respectable distances below the coronary groove implies a distinctive neural control of the ventricles in human and sheep hearts.

Association of echocardiographic atrial size and atrial fibrosis in a sequential model of congestive heart failure and atrial fibrillation

BACKGROUND Cardioversion (CV) success of atrial fibrillation (AF) inversely correlates to the size of the left atrium (LA). Atrial fibrillation and its most important risk factor, congestive heart failure (CHF), both induce atrial structural enlargement and fibrosis. To investigate the effect of AF and CHF on atrial dilatation and fibrosis, and to estimate whether echocardiographically determined atrial size may be used as a marker for atrial fibrosis. METHODS In six dogs, pacemakers were implanted followed by HIS bundle ablation. After 4 weeks of rapid ventricular stimulation (185 bpm) for CHF induction, additional rapid atrial stimulation (500 bpm) was maintained for 7 weeks to induce AF. Serial determinations of echocardiographic atrial size were performed. Seven dogs with sinus rhythm served as histological controls. Postmortem tissue was obtained to determine the degree and composition of atrial fibrosis. RESULTS While the ejection fraction of the AF/CHF dogs decreased significantly from 57+/-5% to 19+/-7% (P<.01), an increased degree of atrial fibrosis was found (right atrium [RA], 4.9+/-2.0% to 19.9+/-5.4%; LA, 4.4+/-1.6% to 22.2+/-3.2%; P<.01), accompanied by a significant increase of atrial volumes (LA: 21+/-4 to 44+/-4 mm3; P<.01; RA: 10+/-3 to 18+/-6 mm3; P<.05) and LA diameters (34+/-4 to 43+/-2 mm, P<.05). Atrial fibrosis and size significantly correlated. CONCLUSIONS Atrial fibrillation/CHF leads to a significant atrial fibrosis and dilation. The increased echocardiographic size correlates to the degree of atrial fibrosis and may be used as clinical marker for atrial fibrosis. The fibrosis accompanying atrial dilatation may also explain why LA size, as determined by echocardiography, is a strong predictor of CV success.

Development and validation of the Rasch-based depression screening (DESC) using Rasch analysis and structural equation modelling

Questionnaires for the assessment of depression benefit from modern test construction like item-response-modelling. We developed two parallel 10 item depression questionnaires, the Rasch-based Depression Screening version 1 (DESC-I) and 2 (DESC-II), by combining Rasch analysis and structural equation modelling on patient samples suffering primarily from a mental disorder or from somatic diseases. Both scales base upon a Rasch homogeneous item bank and proved unidimensionality and good model fit. Cut-off scores with good sensitivity and specificity were developed using ROC analyses. Results suggest that DESC may be appropriately used to screen for depression and may be beneficial for repeated measurements.

Bioelectrical impedance spectroscopy as a fluid management system in heart failure

Episodes of hospitalization for heart failure patients are frequent and are often accompanied by fluid accumulations. The change of the body impedance, measured by bioimpendace spectroscopy, is an indicator of the water content. The hypothesis was that it is possible to detect edema from the impedance data. First, a finite integration technique was applied to test the feasibility and allowed a theoretical analysis of current flows through the body. Based on the results of the simulations, a clinical study was designed and conducted. The segmental impedances of 25 patients suffering from heart failure were monitored over their recompensation process. The mean age of the patients was 73.8 and their mean body mass index was 28.6. From these raw data the model parameters from the Cole model were deduced by an automatic fitting algorithm. These model data were used to classify the edema status of the patient. The baseline values of the regression lines of the extra- and intracellular resistance from the transthoracic measurement and the baseline value of the regression line of the extracellular resistance from the foot-to-foot measurement were identified as important parameters for the detection of peripheral edema. The rate of change of the imaginary impedance at the characteristic frequency and the mean intracellular resistance from the foot-to-foot measurement were identified as important parameters for the detection of pulmonary edema. To classify the data, two decision trees were considered: One should detect pulmonary edema (n(pulmonary) = 13, n(none) = 12) and the other peripheral edema (n(peripheral) = 12, n(none) = 13). Peripheral edema could be detected with a sensitivity of 100% and a specificity of 90%. The detection of pulmonary edema showed a sensitivity of 92.31% and a specificity of 100%. The leave-one-out cross-validation-error for the peripheral edema detection was 12% and 8% for the detection of pulmonary edema. This enables the application of BIS as an early warning system for cardiac decompensation with the potential to optimize patient care.

Dilatation of the pulmonary veins in atrial fibrillation: a transesophageal echocardiographic evaluation.

Ectopic beats originating from sleeves of atrial tissue within the pulmonary veins (PVs) can induce and sustain paroxysmal atrial fibrillation (AF). Left atrial stretch and dilatation favors the development of atrial ectopy and AF. Similarly, PV dilatation, if present, might trigger PV ectopy in patients with AF. This study was designed to evaluate whether PV dilatation is present in patients with nonfocal AF and whether the PV diameter correlates to the left atrial diameter (LAD). The diameters of the right superior (RSPV) and left superior PV (LSPV) were measured at the ostium and at a depth of 1 cm in 170 patients (AF, n = 75 ; sinus rhythm [SR], n = 95) using transesophageal echocardiography. The LAD was determined by transthoracic echocardiography. The diameters of the PVs were significantly larger in patients with AF than in patients with SR (LSPVostium: AF 13.6 ± 3.5 mm vs SR 10.6 ± 2.7 mm, P < 0.001 ; LSVP1cm: AF 12.5 ± 2.9 mm vs SR 10.2 ± 2.5 mm, P < 0.001 ; RSPVostium, AF 13.9 ± 3.5 mm vs SR 11.7 ± 2.9 mm, P < 0.001 ; RSVP1cm: AF 12.8 ± 2.8 mm vs SR 10.6 ± 2.6 mm, P < 0.05). Similarly, LAD was larger in patients with AF (44.7 ± 7.7 mm) as compared to patients with SR (38.8 ± 6.8 mm, P < 0.001). Neither for the SR nor the AF group did the PV size correlate to the LAD. AF is associated with a significant enlargement of the RSPV, LSPV, and LAD. There is no correlation between LAD and PV diameters. This raises the question whether PV dilatation in patients with AF is a cause or a consequence of AF and whether it may contribute to the development and perpetuation of AF. (PACE 2003; 26:1371–1378)

Telephonic transmission of 12-lead electrocardiograms during acute myocardial infarction:

To test the feasibility of a small and simple system for telephonic transmission of 12-lead electrocardiograms (ECGs), 70 patients with acute coronary syndrome admitted to the cardiac care unit (CCU) were included in a feasibility study. The transmission system consisted of a belt with multiple electrodes, which was positioned around the chest. The ECG signal was sent to a call centre via a standard telephone line. In parallel, a standard 12-lead ECG was recorded on site. In a retrospective analysis, each lead of the transmitted ECG was compared with the on-site 12-lead ECG with regard to ST-segment changes and final diagnosis. In all 37 patients with acute ST-elevation myocardial infarction, the diagnosis was correctly established on the basis of telephone-transmitted ECGs. In 96% of limb and 88% of chest leads, ST elevations which were visible in standard ECGs were correctly displayed on telephonically transmitted ECGs. In the remaining 33 patients no false-positive diagnosis was made using transtelephonic ECG analysis. A control group of 31 patients without apparent heart disease showed high concordance between standard ECGs and telephonically transmitted ECGs. Telephonically transmitted 12-lead ECGs interpreted by a hospital-based internist/cardiologist might allow a rapid and accurate diagnosis of ST-elevation myocardial infarction and may increase diagnostic safety for the emergency staff during prehospital decision making and treatment of acute myocardial infarction.

Integration of Automatic Intrathoracic Fluid Content Measurement into Clinical Decision Making in Patients with Congestive Heart Failure

Background: Hospitalizations due to decompensation are a frequent problem in treating patients with congestive heart failure (CHF). Continuous impedance measurement via implantable devices may detect pulmonary fluid accumulation due to worsening CHF. An acoustic alert might allow an earlier treatment of impending decompensation. An algorithm that implemented impedance measurement into clinical decision making in treating CHF patients was evaluated.

Neurofilament light chain as an early and sensitive predictor of long-term neurological outcome in patients after cardiac arrest

BACKGROUND Neurofilament light chain (NF-L) is the major intermediate filament specifically expressed in neurons and their axons. No data are available concerning serum levels of NF-L after global cerebral ischemia due to cardiac arrest. To find a specific neuronal marker of long-term neurological outcome, we examined serum levels of NF-L in patients after cardiac arrest. METHODS A prospective observational cohort study was conducted. Blood samples for the measurement of NF-L were analyzed from 85 patients within 2h after admission, as well as on 2nd, 3rd, 5th, and 7th day. Neurological outcome was assessed 6 months after cardiac arrest by employing the Modified Glasgow Outcome Score (MGOS). RESULTS The serum course of NF-L in patients with poor neurological outcome (MGOS 1+2) was significantly augmented compared to patients with good neurological outcome (MGOS 3+4+5) (on admission (pg/ml): good: 125 ± 11.7 vs. poor: 884.4 ± 86.2 pg/ml; 3rd day: good: 153.1 ± 13.2 vs. poor: 854.4 ± 119.1; 7th day: good: 112.5 ± 10.4 vs. poor: 1011.8 ± 100.8; P<0.001). Intermediate NF-L serum values were found in patients with MGOS 0, which represents a mixture of patients who died with and without certified brain damage (on admission (pg/dl): 433.7 ± 49.8; 3rd day: 598.3 ± 86.6; 7th day: 474 ± 77.4). A prediction power of 0.93 (c-statistic, 95%-CI 0.87-0.99) on 1st, 0.85 (0.81-0.95) on 2nd, 0.92 (0.85-0.99) on 3rd, 0.97 (0.92-1) on 5th and 0.99 (0.98-1) on 7th day was achieved for NF-L predicting poor neurological outcome. CONCLUSIONS The present data suggest that within 7 days after cardiac arrest serum NF-L is a valuable marker of long-term neurological outcome.