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Depression is more common in patients with cardiovascular disease than in the general population. Conversely, depression is a risk factor for developing cardiovascular disease. Comorbidity of these two pathologies worsens prognosis. Several mechanisms have been indicated in the link between cardiovascular disease and depression, including inflammation. Systemic inflammation can have long-lasting effects on the central nervous system, which could be associated with depression. NGAL is an inflammatory marker and elevated plasma levels are associated with both cardiovascular disease and depression. While patients with depression show elevated NGAL levels, in patients with comorbid heart failure, NGAL levels are significantly higher and associated with depression scores. Systemic inflammation evokes NGAL expression in the brain. This is considered a proinflammatory effect as it is involved in microglia activation and reactive astrocytosis. Animal studies support a direct link between NGAL and depression/anxiety associated behavior. In this review we focus on the role of NGAL in linking depression and cardiovascular disease.

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In this review we discuss the position of electrical neuromodulation as a safe and reversible adjuvant therapy for treatment of patients with chronic cardiac diseases who have become refractory to conventional strategies. In patients with chronic refractory angina, electrical neuromodulation, independent of the applied modality, has shown to reduce complaints of angina, to enhance exercise capacity, to improve quality of life and to employ anti-ischaemic effects. To date, electrical neuromodulation seems to be one of the best adjuvant therapies for these patients. In addition, neuromodulation in the treatment of heart failure and resistant arrhythmias is the subject of several ongoing studies.

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Our objective was to determine whether electrical neuromodulation using spinal cord stimulation (SCS) mitigates transient ischemia-induced ventricular infarction and, if so, whether adrenergic neurons are involved in such cardioprotection. The hearts of anesthetized rabbits, subjected to 30 min of left anterior descending coronary arterial occlusion (CAO) followed by 3 h of reperfusion (control), were compared with those with preemptive SCS (starting 15 min before and continuing throughout the 30-min CAO) or reactive SCS (started at 1 or 28 min of CAO). For SCS, the dorsal C8-T2 segments of the spinal cord were stimulated electrically (50 Hz, 0.2 ms, 90% of motor threshold). For preemptive SCS, separate groups of animals were pretreated 15 min before SCS onset with 1) vehicle, 2) prazosin (alpha(1)-adrenoceptor blockade), or 3) timolol (beta-adrenoceptor blockade). Infarct size (IS), measured with tetrazolium, was expressed as a percentage of risk zone. In controls exposed to 30 min of CAO, IS was 36.4 +/- 9.5% (SD). Preemptive SCS reduced IS to 21.8 +/- 6.8% (P < 0.001). Preemptive SCS-mediated infarct reduction was eliminated by prazosin (36.6 +/- 8.8%) and blunted by timolol (29.4 +/- 7.5%). Reactive SCS did not reduce IS. SCS increased phosphorylation of cardiac PKC. SCS did not alter blood pressure or heart rate. We conclude that preemptive SCS reduces the size of infarcts induced by transient CAO; such cardioprotection involves cardiac adrenergic neurons.

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BACKGROUND/OBJECTIVES: Clinical data have shown that electrical neurostimulation may improve myocardial ischaemia. Our aim was to investigate the possible effect of electrical neurostimulation on collateral perfusion. METHODS: Thirty patients with stable angina and significant single-vessel coronary artery disease scheduled for elective percutaneous coronary intervention (PCI) were randomised into three groups. In all patients two balloon inflations were performed, one for predilatation of the lesion, the second for stent delivery. Group one received active neurostimulation during the first ischaemic episode (predilatation), group two during the second ischaemic episode (stent delivery), and group three received placebo neurostimulation continuously. During both ischaemic episodes the collateral flow index was determined. RESULTS: No significant differences were found between active, inactive or placebo neurostimulation. In a post-hoc analysis the patients were stratified for presence or absence of significant collaterals. In patients with pre-existing significant collaterals, the collateral flow index was significantly higher during active neurostimulation compared with inactive neurostimulation (p=0.012) and compared with the merged inactive and placebo groups (p=0.011). CONCLUSION: The present data show no effect of electrical neurostimulation on collateral perfusion in patients with single-vessel disease. In a post-hoc analysis in patients with evidence of collaterals, defined as a collateral flow index of >0.24, an increase in collateral perfusion was found during electrical neurostimulation.

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At present, there is no reliable antianginal drug therapy for patients with cardiac syndrome X. Therefore, the effect of electrical neuromodulation on refractory angina pectoris and myocardial perfusion in cardiac syndrome X was assessed. Eight patients (aged 55+/-7 years) with heterogeneous myocardial perfusion and no esophageal abnormalities were included. The subjects were nonresponders to antianginal drug therapy. Angina pectoris attacks and myocardial perfusion dynamics were evaluated by positron emission tomography at baseline and following 4 weeks of (transcutaneous electrical nerve stimulation) TENS. Following TENS there was a reduction of angina pectoris episodes (baseline 20+/-3, TENS 3+/-1; p=0.012), and short acting nitroglycerin intake per week (baseline 10+/-3, TENS 2+/-1; p=0.008). The rate pressure product (mmHg min(-1)) during the cold pressor test (CPT) was reduced during TENS (baseline 12800+/-1200, TENS 11500+/-900; p=0.02). Following TENS, the perfusion reserve ratio between rest and dipyridamole flow increased (baseline 1.59+/-0.15, TENS 1.90+/-0.11 ml min(-1)x 100g; p=0.05). The coronary vascular resistance had a trend towards a reduction (baseline 0.96+/-0.04, TENS 0.85+/-0.06 mmHg min(-1)x 100 g/ml; p=0.06) during CPT. This observation may suggest that neurostimulation improves angina pectoris with a concomitant improvement of myocardial perfusion in cardiac syndrome X.

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Patients with heart failure have, in spite of improved palliative therapies, bad prognosis. Cardiac tissue engineering by use of a temporary bioscaffold and cardiomyocytes may help to find answers for future treatments in heart failure. For that purpose two neonatal rat heart ventricular cell fractions were obtained after a gradient cell separation. Time related characteristics of Fractions I and II were established in two-dimensional (2-D) and three-dimensional (3-D) cell cultures. The 3-D cardiac constructs were obtained by use of a bovine type I collagen matrix after culturing either under static conditions or in the HARV bioreactor. With the 2-D cultures contracting cells were present after 1 day, and reached confluency from day 5 on and this was maintained up to 135 days. In Fraction-I some non-contracting cells were always noticed between the (in time in unison) contracting cells. Transmission electron microscopy (TEM) revealed that these mainly concerned fibroblasts. Differences in the expression of alpha-SM-1 actin and troponin-T were observed between the two fractions. In both fractions endothelial cells and macrophages were only sporadically observed. All through the 3-D matrix pendant-like single cell and clustered cell contractions were present after 1-2 days, resulting in time in unison contracting of cells with the collagen matrices. The whole event was faster with Fraction-I and was observed up to 3 weeks. At this time point clusters of troponin-T positive cells were found scattered through the collagen matrices. Additionally, TEM revealed healthy layers of connected cardiomyocytes with intercalated discs, in this case on and in between the collagen fibres. These findings provide evidence that in unison contracting structurally organized cell-matrix cardiac constructs can be engineered by use of co-cultures (neonatal cardiomyocytes and fibroblasts) and collagen matrices, which is very promising for the repair of larger scar areas of the myocardium.

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Electrical excitation of the dorsal aspect of the rostral thoracic spinal cord imparts long-term therapeutic benefits to patients with angina pectoris. Such spinal cord stimulation also induces short-term suppressor effects on the intrinsic cardiac nervous system. The purpose of this study was to determine whether spinal cord stimulation (SCS) induces long-term effects on the intrinsic nervous system, particularly in the presence of myocardial ischaemia. The activity generated by right atrial neurons was recorded in 10 anesthetized dogs during basal states, during prolonged (15 min) occlusion of the left anterior descending coronary artery, and during the subsequent reperfusion phase. Neuronal activity and cardiovascular indices were also monitored when the dorsal T1-T4 segments of the spinal cord were stimulated electrically (50 Hz; 0.2 ms) at an intensity 90% of motor threshold (mean 0.32 mA) for 17 min. SCS was performed before, during and after 15-min periods of regional ventricular ischaemia. Occlusion of a major coronary artery, one that did not perfuse investigated neurons, resulted in their excitation. Ischaemia-induced neuronal excitatory effects were suppressed (-76% from baseline) by SCS. SCS suppression of intrinsic cardiac neuronal activity persisted during the subsequent reperfusion period; after terminating 17 min of SCS, at least 20 min elapsed before intrinsic cardiac neuronal activity returned to baseline values. It is concluded that populations of intrinsic cardiac neurons are activated by inputs arising from the ischaemic myocardium. Ischaemia-induced activation of these neurons is nullified by SCS. The neuronal suppressor effects that SCS induces persist not only during reperfusion, but also for an extended period of time thereafter. These long-term effects may account, in part, for the fact that SCS imparts clinical benefit to patients with angina of cardiac origin not only during its application, but also for a time thereafter.

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OBJECTIVES: Electrical stimulation of the dorsal aspect of the upper thoracic spinal cord is used increasingly to treat patients with angina pectoris refractory to conventional therapeutic strategies. The purpose of this study was to determine whether spinal cord stimulation (SCS) in dogs affects regional myocardial blood flow and left-ventricular (LV) function before and during transient obstruction of the left anterior descending coronary artery (LAD). METHODS: In anesthetized dogs, regional myocardial blood flow distribution was determined using radiolabeled microspheres and left-ventricular function was measured by impedance-derived pressure-volume loops. SCS was accomplished by stimulating the dorsal T1-T2 segments of the spinal cord using epidural bipolar electrodes at 90% of motor threshold (MT) (50 Hz, 0.2-ms duration). Effects of 5-min SCS were assessed under basal conditions and during 4-min occlusion of the LAD. RESULTS: SCS alone evoked no change in regional myocardial blood flow or cardiovascular indices. Transient LAD occlusion significantly diminished blood flow within ischemic, but not in non-ischemic myocardial tissue. Left ventricular pressure-volume loops were shifted rightward during LAD occlusion. Cardiac indices were altered similarly during LAD occlusion and concurrent SCS. CONCLUSIONS: SCS does not influence the distribution of blood flow within the non-ischemic or ischemic myocardium. Nor does it modify LV pressure-volume dynamics in the anesthetized experimental preparation.

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We studied the content and distribution of heart-specific markers troponin I and troponin T in relation to conventional non-heart specific myoglobin and alpha-hydroxybutyric acid dehydrogenase (HBD) in the hearts of 34 patients who died of various causes. Tissue was obtained from the right and left ventricles, the interventricular septum, and the right and left atria. We found significant differences in the contents expressed per gram wet weight tissue in the right and left ventricles for troponin I (by 1 of the 2 methods used), troponin T, myoglobin, and HBD and no differences per gram of protein. The biochemical contents per gram wet weight tissue and per gram protein were significantly lower in the right and left atria for all studied markers compared with the right and left ventricles. No significant differences were found in biochemical contents between the right and left atria. These findings imply that estimation of myocardial damage through cardiac markers levels in serum depends on the site of injury (atrium or ventricle). Comparison of myocardial injury among individuals using marker levels in serum is not reliable because of the varied ranges of markers in tissue contents.

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OBJECTIVE: Electrical stimulation of the dorsal aspect of the upper thoracic spinal cord is used increasingly to treat patients with severe angina pectoris refractory to conventional therapeutic strategies. Clinical studies show that spinal cord stimulation (SCS) is a safe adjunct therapy for cardiac patients, producing anti-anginal as well as anti-ischemic effects. However, little information is yet available about the underlying mechanisms involved. METHODS: In order to determine its mechanism of action, the effects of SCS on the final common integrator of cardiac function, the intrinsic cardiac nervous system, was studied during basal states as well as during transient (2 min) myocardial ischemia. Activity generated by intrinsic cardiac neurons was recorded in 9 anesthetized dogs in the absence and presence of myocardial ischemia before, during and after stimulating the dorsal T1-T2 segments of the spinal cord at 66 and 90% of motor threshold using epidural bipolar electrodes (50 Hz; 0.2 ms; parameters within the therapeutic range used in humans). RESULTS: The SCS suppressed activity generated by intrinsic cardiac neurons. No concomitant change in monitored cardiovascular indices was detected. Neuronal activity increased during transient ventricular ischemia (46%), as well as during the early reperfusion period (68% compared to control). Despite that, activity was suppressed during both states by SCS. CONCLUSIONS: SCS modifies the capacity of intrinsic cardiac neurons to generate activity. SCS also acts to suppress the excitatory effects that local myocardial ischemia exerts on such neurons. Since no significant changes in monitored cardiovascular indices were observed during SCS, it is concluded that modulation of the intrinsic cardiac nervous system might contribute to the therapeutic effects of SCS in patients with angina pectoris.

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An increasing number of patients are suffering from angina pectoris that is chronically refractory to standard anti-ischemic treatment such as pharmacological and surgical strategies. To improve the quality of life of these severely disabled patients, without adversely affecting their prognosis, a number of adjunct therapies are available. One of the most promising appears to be spinal cord stimulation. We will review the literature and discuss the efficacy, safety and mechanisms of neuromodulation as an adjuvant therapy for chronic refractory angina pectoris.

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The present study assessed the reoccurrence of myocardial ischemia after withholding electrical neurostimulation. After randomization, in the study or withdrawal group, spinal cord stimulation (SCS) was set active during the first 4 weeks, followed by 4 weeks of withholding stimulation. In the control group, SCS was switched off during 4 weeks before the end of the study. The control group had no crossover period. Measurements were done at baseline, then after 4 and 8 weeks. The first periods at 4 weeks of each sequence of both groups were compared. In addition, a comparison of clinical variables was performed between the study group 4 weeks after withholding stimulation and the control group 4 weeks following randomization. A total number of 24 patients with refractory angina and an implanted spinal cord stimulator were included in the study (n = 12) and control group. Angina pectoris complaints, nitroglycerin intake, ischemia, and heart rate variability using 48-hour ambulatory electrocardiographic monitoring were assessed. In addition, neurohormonal status and symptom-limited aerobic capacity were evaluated. There was no increase of anginal complaints or ischemia after withholding stimulation. Neurohormonal levels and aerobic capacity were not altered. We conclude that there is no adverse clinical rebound phenomenon after withholding neurostimulation in patients with refractory angina pectoris.

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STUDY OBJECTIVE: To measure the pre-hospital delay times in patients with proven acute myocardial infarction (AMI) and to identify possibilities for reduction of treatment delay. DESIGN: Descriptive three centre study. SETTING: One university teaching hospital and two regional hospitals in Groningen, the Netherlands. PATIENTS: 400 consecutive confirmed AMI patients, age below 75 years, admitted to coronary care departments. MAIN RESULTS: Mean age was 59 years and 78% of patients were men. Within two hours after onset of symptoms half of the patients with AMI arrived at the hospital. Patient, doctor, and ambulance delay times (median values) were 30, 38, and 35 minutes respectively. Calling the personal general practitioner (GP) or the locum tenens and whether or not the AMI occurred during a weekend or on a working day had no consequences for pre-hospital delay times. At night patients waited longer before calling a GP than in the daytime. There was a positive correlation between patient and doctor delay. Twenty two per cent of AMI patients waited two hours or more before calling a GP. Total pre-hospital delay times differed between men and women. Longer doctor delay in women (36 minutes for men and 52 minutes for women) was caused by displacement of specific symptoms, in particular in women. AMI patients who were alone during onset of symptoms showed higher patients delay (72 compared with 23 minutes). CONCLUSION: In hospital admitted patients younger than 75 years pre-hospital delay times are within acceptable limits. In some subgroups further reduction is attainable, for example in patient delay outside office hours and when patients are alone during onset of symptoms, in doctor delay in cases where women present with symptoms suggestive for AMI. Improvement of facilities for pre-hospital electrocardiographic diagnosis may facilitate decision making by GPs. Good opportunities for further reduction of treatment delay exist in shortening of hospital delay.

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OBJECTIVE: To determine morbidity and mortality characteristics in patients treated with electrical neuromodulation for refractory angina pectoris. DESIGN: A retrospective multicentre study of patients treated with spinal cord stimulation between 1987 and 1997; 21 centres were contacted and 14 responded. SETTING: Specialist centres worldwide. PATIENTS: Questionnaires were returned on 517 patients, of whom 71% were male. One was lost to follow up. Mean (SD) age was 63.9 (10.1) years. Duration of angina pectoris was 8.1 (6.3) years. RESULTS: Before spinal cord stimulation, 66% of the patients had experienced myocardial infarction, 68% had three vessel disease, and in 24% the left ventricular ejection fraction (LVEF) was /= 71 years were independent predictors of mortality. During spinal cord stimulation, New York Heart Association functional class improved from 3.5 to 2.1 (p < 0.01); 25 of the deceased patients (24%) and 32 survivors (8%) experienced myocardial infarction; hospital admissions were significantly (p < 0.001) more common in the deceased group (66% v 37%). CONCLUSIONS: The clinical outcome of patients with intractable angina is not adversely affected by the chronic use of neurostimulation.

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Objective. For patients with refractory angina pectoris, spinal cord stimulation (SCS) is a beneficial and safe adjuvant therapy. However, it has not yet been established whether SCS alters the quality of life (QoL) in these patients. Methods. In this study, 26 consecutive patients (age 61.3 ± 7.0 years, 13 females, angina duration 12.7 ± 6.0 years) were recruited. Social, mental, and physical aspects of QoL were determined by Nottingham Health Profile (NHP I), depression scale (CES-D), scoring of angina pectoris attacks and short-acting nitroglycerine intake, pain score on the Visual Analog Scale (VAS), perceived health percentage, Satisfaction With Life scale (SWLS), and one-aspect Linear Analog Self Assessment scale (LASA). QoL outcomes at baseline were compared with reference values from healthy subjects. Within-group changes and magnitude of changes (effect size, ES) were assessed after 3 months and 1 year of SCS. Results. Compared to healthy subjects, the patients had significantly worse scores at baseline on NHP, SWLS, and LASA. After 3 months of SCS, NHP I aspect pain (ES = 1.39), AP-score (ES = 0.85), perceived health percentage (ES =- 0.80), NTG-use (ES = 1.08) and VAS-score (ES = 1.13) were all significantly improved (p < 0.05). After 3 months, moderate changes were observed; however, they were not statistically significant on the NHP-aspects "emotion" (ES = 0.57) and "sleep" (ES = 0.56). At the 1-year follow-up, significant and substantial improvements were found on NHP-I aspects: pain, energy, emotional reactions, social isolation, sleep, and physical mobility (p < 0.05) with changes that can be interpreted as large (ES > 0.80). Conclusion. QoL in patients with refractory angina pectoris is poor. Both pain and health aspects of QoL improved significantly after 3 months of SCS. Social, mental, and physical aspects of QoL were found improved after 1 year of SCS.

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Patients with symptomatic small vessel coronary artery disease may be inadequate candidates for revascularization procedures. They may suffer from refractory angina, which does not respond to maximal anti-anginal drug therapy. In addition to patients with end stage coronary artery disease and syndrome X, this newly defined group of subjects with an isolated stenosis of a small coronary artery may benefit from electrical neurostimulation. We describe two patients with intractable angina caused by a significant narrowing of a diagonal branch. This treatment modality should be considered as an alternative method for unsatisfactory revascularization procedures.

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BACKGROUND: Spinal cord stimulation is known to be a successful treatment for chronic intractable angina pectoris. Its effect may be anti-ischemic. It is uncertain if the clinical effect is partly caused by a placebo effect of surgery for implantation of a stimulator. In this study, clinical efficacy is investigated, together with a possible placebo effect. METHODS AND RESULTS: Efficacy of spinal cord stimulation as a treatment for chronic intractable angina pectoris was studied for 6 weeks in 13 treated patients and 12 control patients with chronic angina. Assessments were exercise capacity and ischemia, daily frequency of anginal attacks and nitrate tablet consumption, and quality of life (perceived quality of life and pain). Compared with control, exercise duration (P =.03) and time to angina (P =.01) increased; anginal attacks and sublingual nitrate consumption (P =.01) and ischemic episodes on 48-hour electrocardiogram (P =.04) decreased. ST-segment depression on the exercise electrocardiogram decreased at comparable workload (P =.01). Anginal attacks and consumption of sublingual nitrates decreased (P =.01), perceived quality of life increased (P =.03), and pain decreased (P =.01). CONCLUSIONS: Spinal cord stimulation is effective in chronic intractable angina pectoris, and its effect is exerted through anti-ischemic action. Efficacy is unlikely to be explained as a placebo effect from surgery.

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Myocardial contusion is an infrequent, but sometimes serious complication in patients who experienced deceleration (blunt) trauma. We investigated the assessment of the new cardiac markers troponin I (cTnI) and troponin T (cTnT) in relation to the conventional CKMB-activity, the CKMB-activity/CK-total ratio, CKMB-mass and the CKMB-mass/CK-total ratio for the detection of myocardial contusion in 89 patients with blunt trauma (38 patients with thoracic injuries and 51 patients without thoracic injuries). All parameters were analysed at admission (t1) and 24 h after admission (t2). For the patients with thoracic injuries, at t1 cTnI was elevated in three, and cTnT in four patients; at t2 both cTnI and cTnT were elevated in nine patients. At t1, eighteen to thirty patients had increased levels of the conventional parameters; at t2 this was true for six to thirty-five patients. For the patients without thoracic injuries all cTnI and cTnT levels were within the reference ranges at t1. At t2 one patient, who experienced an acute myocardial infarction, had elevated cTnI and cTnT levels. At t1, five to thirty-five patients had increased levels of the conventional parameters; at t2 this was true for four to forty-two patients. From this study we conclude that the conventional parameters are not useful for the detection of myocardial contusion in patients experiencing blunt trauma. The parameters cTnI and cTnT are equally accurate and more reliable for the selection of patients who require intensive cardiac monitoring. If at admission the cTnI or the cTnT levels are within the reference ranges, a second analysis after admission is necessary to reach a reliable conclusion concerning myocardial contusion as a result of trauma on basis of the troponin levels.

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