Impact of biomarkers for endothelial dysfunction and procoagulant state on 10-year cardiovascular risk in Type 2 diabetes.

AIMS: To estimate the coronary heart disease and cardiovascular disease risk associated with novel biomarkers in Type 2 diabetes mellitus. METHODS: We measured baseline peripheral blood concentrations of soluble E-selectin, factor XIIa, thrombin-antithrombin III complex and plasminogen activator inhibitor-1 in 86 patients with Type 2 diabetes free of known coronary heart disease. We used Cox proportional hazard models to estimate multivariable-adjusted hazard ratios associated with biomarker levels for 10-year coronary heart disease risk (n = 33 events) or total cardiovascular disease risk (n = 45 events). RESULTS: At baseline, mean (sd) age was 62 years (7 years); 62 were men; and 43 had microalbuminuria. Soluble E-selectin demonstrated cross-sectional relationships with glucose and factor XIIa was related to plasminogen activator inhibitor-1 and triglycerides (all P < 0.05). Baseline log soluble E-selectin was significantly related to incident coronary heart disease and cardiovascular disease. Hazard ratios (95% CIs) associated with a 1-unit increase in log soluble E-selectin in age- and sex-adjusted models were: coronary heart disease : 4.6 (95% CI 1.9-11.3), P = 0.001; cardiovascular disease: 3.6 (95% CI 1.7-7.4, P = 0.001); and in multivariable-adjusted models were: coronary heart disease: 2.9 (95% CI 1.2-7.1, P = 0.02); cardiovascular disease: 2.3 (95% CI 1.1-4.8), P = 0.02. Factor XIIa was significantly related to incident cardiovascular disease. The hazard ratios associated with a 1-unit increase in factor XIIa in age- and sex-adjusted models was 1.5 (95% CI 1.1-1.9, P = 0.003) and in a multivariable-adjusted model was 1.3 (95% CI 1.0-1.6, P = 0.047). Plasminogen activator inhibitor-1 and thrombin-antithrombin III complex were not related to cardiovascular disease events. CONCLUSIONS: In our study, soluble E-selectin and factor XIIa were significantly related to 10-year incident macrovascular events in patients with Type 2 diabetes. These preliminary findings call for replication in larger studies.

Delays and adverse clinical outcomes associated with unrecognized pacing indications.

BACKGROUND: A recent UK audit showed that a significant proportion of patients who received pacemakers had pacing indications previously overlooked, leading to significant delays to pacemaker implantation. AIM: To investigate the reasons for, and morbidity associated with, overlooked pacing indications. DESIGN: Prospective observational study in a UK regional pacing centre and its referring district hospitals. METHODS: Hospital records from referring and implanting centres were reviewed for 95 consecutive patients undergoing first pacemaker implant to determine symptoms, investigations and hospitalisations occurring after documentation of a pacing indication. RESULTS: Thirty-three of ninety-five patients (35%) had a pacing indication overlooked, which was Class I in 14 patients and Class IIa in 19. Reasons for not making a pacing referral in these patients included: failure to recognize the indication in 14, making adjustments to potentially culprit medication in 15 and requesting additional 'confirmatory' tests in 4. Twenty-six patients (79%) with missed indications experienced adverse events after documentation of an indication, and before receiving a pacemaker: 23 had ongoing symptoms (including one cardiac arrest), three received temporary pacing wires and 18 were hospitalized with symptoms related to cardiac rhythm. Twenty-seven patients (82%) had a total of 38 additional specialist investigations after documentation of a pacing indication. CONCLUSION: Documentation of an indication for pacing failed to trigger referral for permanent pacing in 35% of patients. This failure led to significant delays, morbidity and use of health service resource, which may have been avoided if timely recognition of the pacing indication had prompted referral. Failure to recognize pacing indications and reassessing symptoms and repeating investigation after changes to medication, often required for the management of associated tachyarrhythmias or other medical conditions, contribute to these delays, perhaps unnecessarily.

The patient journey from symptom onset to pacemaker implantation.

BACKGROUND: Regional variation in permanent pacemaker (PPM) implantation rates is well described, the reasons for which are unclear. Significant delays to PPM implantation in UK practice were described 20 years ago, but contemporary data are lacking. AIM: To investigate delays to PPM implantation and their causes. DESIGN: Prospective observational study in a UK regional pacing centre and its referring district hospitals. METHODS: A total of 95 consecutive patients receiving first PPM implant for bradycardia indications from 1 June 2006 to 31 August 2006 were included. Hospital records from the referring and implanting centres were reviewed to determine the timings of: symptom onset; first hospital contact; documented pacing indication (defined by 2002 ACC/AHA/NASPE guidelines); referral to implanter; and PPM implantation. RESULTS: Forty-eight patients (51%) were referred for pacing urgently; median delay from symptoms to PPM 15 days (range 0-7332 days). Forty-seven patients (49%) were referred electively; median delay from symptoms to PPM 380 days (range 33-7505 days), P < 0.0001. Twenty-three of the 47 elective patients (49%) had previous hospitalization with symptoms suggestive of bradycardia. Thirty-three of the 95 patients (35%) had a Class I or IIa pacing indication which did not trigger a pacing referral. CONCLUSION: There are significant delays to PPM implantation in the United Kingdom, longer in those treated electively than those managed as emergencies. Some delays are due to 'process' problems including waiting lists, but a substantial proportion of patients had delays due to failure to refer for pacing once a pacing indication was documented.

Sudden cardiac death: opportunities for prevention.

The evidence base for implantable cardioverter-defibrillator (ICD) therapy requires expansion of guidance/indications to allow UK physicians to treat a broader range of patients. The ICD clinical consultees to the National Institute for Health and Clinical Excellence (NICE) review current guidance/guidelines, explain the evidence base, and suggest a UK ICD implantation strategy.

The implantable cardioverter-defibrillator: postcode prescribing in the UK 1998-2002.

OBJECTIVE: To determine the rate of implantable cardioverter-defibrillator (ICD) implantation across the UK during the period 1998 to 2002. DESIGN: Observational self reporting with cross checking. SETTING: All ICD implanting centres coordinated by the National Pacemaker and ICD Database. PATIENTS: Every patient receiving an ICD in the UK from 1998 to 2002. MAIN OUTCOME MEASURES: Date of implantation and postcode of each ICD recipient during the study period. RESULTS: ICD implantation increased in the UK in the five year period studied but fell far short of the European average and national targets. Implantation rates varied greatly by region. CONCLUSIONS: The low rate of ICD implantation in the UK and the disparity between regions require further study to determine the barriers to this evidence based treatment.

Individualised quality of life after pacing. Does mode matter?

AIMS: To examine the hypothesis that atrial based pacing improves Quality of Life (QoL) after pacing by undertaking a detailed QoL evaluation that includes an individualised assessment as well as disease specific evaluation. METHODS: Prospective study of patients randomised to VVI(R) or atrial based pacing modes using the Schedule for the Evaluation of Individual QoL (SEIQoL), the 36-item Medical Outcomes Study Short-Form General Health Survey (SF36), and a modified version of the Karolinska Cardiovascular Symptomatology Questionnaire (KCSQ). RESULTS: Seventy-three patients completed the two-year follow up of the study. Pacing improved SEIQoL scores, cardiovascular symptoms and the physical role limitation, social limitation and mental health domains of SF36 from baseline to one month. Pacing mode had no effect on QoL the major determinants of which were baseline QoL and a history of coronary artery disease. CONCLUSION: Atrial based pacing does not improve QoL in the two years after pacing when compared with VVI(R) pacing.

Detection of atrial fibrillation by permanent pacemakers: observations from the STOP AF trial.

Pacemaker telemetry is increasingly being used to infer the presence or absence of arrhythmias in clinical practice. To evaluate the reliability of these data in patients with sick-sinus syndrome, a sub-study of eighteen consecutive patients in the Systematic Trial of Pacing to prevent Atrial Fibrillation (STOP AF) implanted with dual-chamber pacemakers had simultaneous 24-hour Holter recordings and pacemaker telemetry down-loaded. Whilst heart rate data were very similar, telemetry data achieved only 57% sensitivity with 64% specificity for the presence of atrial fibrillation on Holter recording over 24 hours. False-positive results were due to far-field sensing while false-negatives were seen with very short episodes of atrial fibrillation. The pacemaker's anti-tachycardia responses were not specific for the detection of atrial fibrillation. There are very few published reports correlating pacemaker diagnostic data and stored electrograms with external Holter monitoring. We believe that more validation studies of are needed before pacemaker diagnostic data can be used with confidence in clinical practice. It is unlikely that current devices with sophisticated detection algorithms will fail to detect prolonged episodes of arrhythmia and their capacity to confirm events with stored electrograms, intervals and markers reduces the possibility of false-positives, but care must be taken in the interpretation of stored data from devices without these capabilities. Equally, it cannot be assumed that if intracardiac electrograms from one episode confirm the presence of an arrhythmia, that all recorded events have been similarly correctly interpreted. We have shown in a sub-study of STOP-AF that simple mathematical models using heart rate bin analysis are not reliable for detection of arrhythmias with short durations. Despite these limitations, the potential of implanted pacemakers to record cardiac rhythm and trends, such as heart-rate variability, over time remains an exciting prospect, particularly in guiding individual patient therapy.

The use of permanent pacemakers in the detection of cardiac arrhythmias.

AIMS: To compare pacemaker telemetry with simultaneous Holter recordings in the diagnosis of atrial fibrillation and to evaluate the STOP-AF study telemetry criteria for the presence of atrial fibrillation. METHODS AND RESULTS: 18 consecutive patients enrolled in the STOP-AF study had simultaneous 24 h Holter recordings and down-loaded pacemaker telemetry. There was good agreement on heart rate, but the STOP-AF pacemaker criteria achieved only 57% sensitivity with 64% specificity for the presence of atrial fibrillation on Holter recording over 24 h. False-positives appeared to result from far-field sensing while false-negatives occurred with very short episodes of atrial fibrillation. The pacemaker's antitachycardia responses were not specific for the presence of atrial fibrillation. CONCLUSION: Pacemaker telemetry is a potentially important source of data on cardiac arrhythmias. Further studies are required to define the limitations of these data in specific devices before they can be interpreted with confidence.

Low-frequency heart rate variability: reproducibility in cardiac transplant recipients and normal subjects.

Heart rate variability is a measure of autonomic nervous influence on the heart. It has been suggested that it could be used to detect autonomic reinnervation to the transplanted heart, but the reproducibility of the measurement is unknown. In the present study, 21 cardiac transplant recipients and 21 normal subjects were recruited. Three measurements of heart rate variability were performed during the day: in the morning, in the early afternoon and in the late afternoon. These tests were then repeated 1 week later and then again 1 week after that, making nine tests in all. The within-subject S.D. was 0.49 log units in normal subjects and 0.79 log units in transplant recipients. In both cases, this is about 15% of the population range. There was significant variation in heart rate variability between different times of day in both groups, and from day to day in transplant recipients. It was concluded that the reproducibility of measurements of heart rate variability is low, and that differences between measurements performed at different times of day should be interpreted with caution.

Heart rate and blood pressure variability in normal subjects compared with data from beat-to-beat models developed from de Boer's model of the cardiovascular system.

The objective of this study was to assess the ability of de Boer's model of the cardiovascular system to reproduce the heart rate and blood pressure variability observed in a range of normal subjects, and to make modifications to improve its performance. ECG, blood pressure and chest wall movement were recorded from 12 normal human subjects during controlled breathing. For each beat, systolic pressure, diastolic pressure, arterial time constant and RR interval were extracted. RR interval and systolic pressure spectral power in low and high frequency bands and the baroreflex sensitivity index, alpha, were then determined. For each subject, mean values were input to the model and the beat-to-beat output compared with the actual data for that subject. Finally, the effects of reducing the influence of baroreflex on peripheral vascular resistance and of providing separate sympathetic and vagal baroreflex sensitivities were assessed. Simulations resulted in data which were qualitatively similar to those of each subject's recording. With the modifications, the log ratio of simulated to real data improved from 7.2 to 1.5 (p = 0.003) for low frequency RR, from 0.27 to 0.55 (p = 0.011) for high frequency RR and from 8.5 to 0.9 (p = 0.003) for low frequency systolic pressure. We conclude that de Boer's model reproduces many of the characteristics of heart rate and blood pressure variability, and our modifications to baroreflex sensitivities and the feedback effect on peripheral resistance resulted in significant improvements.

Increased left ventricular mass index and nocturnal systolic blood pressure in patients with Type 2 diabetes mellitus and microalbuminuria.

AIMS: To compare left ventricular mass (LVM) index and function in patients with Type 2 diabetes mellitus with and without microalbuminuria and to investigate the clinical determinants of left ventricular hypertrophy. METHODS: Echocardiography, electrocardiography and 24-h ambulatory blood pressure monitoring were performed in microalbuminuric (n = 29) and normoalbuminuric (n = 29) patients with Type 2 diabetes and no clinical evidence of heart disease. Groups were individually matched for age, sex and diabetes duration and smoking status. RESULTS: LVM index (62 (34-87) vs. 52 (33-89) g/m2.7, P = 0.04) and LVH prevalence, using two out of three definitions, were greater in patients with microalbuminuria (LVM/height2.7: 72 vs. 59%, P = 0.27, LVM/height: 66 vs. 38%, P = 0.04, LVM/body surface area: 59 vs. 31%, P = 0.03). Night-time systolic blood pressure (126 (99-163) vs. 120 (104-157) mmHg, P = 0.005) and the night/day systolic blood pressure ratio (0.92 (0.08) vs. 0.88 (0.06), P = 0.04) were higher in those with microalbuminuria. Systolic and diastolic function were similar in both groups. Linear regression analyses showed that body mass index (BMI) was significantly related to loge LVM index (R2 = 11.8%, P = 0.005) and a relationship with night/day systolic blood pressure was also suggested (R2 = 4.6%, P = 0.057). CONCLUSIONS: In patients with Type 2 diabetes, LVH is more common and severe in those with microalbuminuria. Its presence may be related to raised night/day systolic blood pressure ratio and is significantly related to BMI. The high prevalence of LVH strengthens the case for echocardiographic screening in Type 2 diabetes to identify high risk patients who might benefit from aggressive cardiovascular risk factor intervention.

Surgery for postinfarction ventricular tachycardia in the pre-implantable cardioverter defibrillator era: early and long term outcomes in 100 consecutive patients.

OBJECTIVE: To report outcome following surgery for postinfarction ventricular tachycardia undertaken in patients before the use of implantable defibrillators. DESIGN: A retrospective review, with uniform patient selection criteria and surgical and mapping strategy throughout. Complete follow up. Long term death notification by OPCS (Office of Population Censuses and Statistics) registration. SETTING: Tertiary referral centre for arrhythmia management. PATIENTS: 100 consecutive postinfarction patients who underwent map guided endocardial resection at this hospital in the period 1981-91 for drug refractory ventricular tachyarrhythmias. RESULTS: Emergency surgery was required for intractable arrhythmias in 28 patients, and 32 had surgery within eight weeks of infarction ("early"). Surgery comprised endocardial resections in all, aneurysmectomy in 57, cryoablations in 26, and antiarrhythmic ventriculotomies in 11. Twenty five patients died < 30 days after surgery, 21 of cardiac failure. This high mortality reflects the type of patients included in the series. Only 12 received antiarrhythmic drugs after surgery. Perioperative mortality was related to preoperative left ventricular function and the context of surgery. Mortality rates for elective surgery more than eight weeks after infarction, early surgery, emergency surgery, and early emergency surgery were 18%, 31%, 46%, and 50%, respectively. Actuarial survival rates at one, three, five, and 10 years after surgery were 66%, 62%, 57%, and 35%. CONCLUSIONS: Surgery offers arrhythmia abolition at a risk proportional to the patient's preoperative risk of death from ventricular arrhythmias. The long term follow up results suggest a continuing role for surgery in selected patients even in the era of catheter ablation and implantable defibrillators.

Erosion of the left ventricle by the epicardial patch of an automatic implantable cardioverter defibrillator.

A 56 year old man with an implantable cardioverter defibrillator was admitted with chest pain and collapse. Erosion of the left ventricle by an epicardial patch was confirmed by thoracotomy, but surgical repair was impossible. This rare complication should be considered in patients with a history of cardioverter defibrillators implanted by thoracotomy.

Identifying patients at low risk of death from cardiac failure after operation for postinfarct ventricular tachycardia.

BACKGROUND: In unselected patients, cardiac failure accounted for most deaths after antiarrhythmic operation (ER) for postinfarction ventricular tachycardia (VT). This study aimed to determine whether patients at low risk of this outcome could be predicted from a retrospective analysis of variables from 100 consecutive ER patients. METHODS: Thirteen variables suggested by other researchers as predictive of outcome were analyzed. At the time of study, ER was the only therapy available for drug refractory VT. RESULTS: Only emergency ER, wall motion score less than 3 and Killip classification were significantly related to death from cardiac failure. The lack of correlation between emergency ER and variables of ER timing, VT less than 24 hours of ER or VT type implies that the need for emergency ER is also related to ventricular dysfunction. Multivariate analysis identified a group at particularly low risk of death with a specificity of 95%. CONCLUSIONS: Patients at low risk of death after ER can be identified prospectively. In the implantable cardioverter defibrillator era, elective ER is best reserved for such patients. Emergency ER may still be justified in younger patients without comorbidity who will die of VT without it.

Effect of pacing mode on morbidity and mortality: update of clinical pacing trials.

Retrospective studies have suggested that, in patients with sick sinus syndrome, it has been recognized that atrial, dual-chamber, or other so-called physiologic modes of pacing are associated with a lower incidence of atrial fibrillation, stroke, heart failure, and death than is single-chamber ventricular pacing. Retrospective data in patients with atrioventricular block are less robust, but still suggest lower mortality and morbidity with dual-chamber pacing compared with ventricular pacing alone. Overall, the reduction in risk of atrial fibrillation with dual-chamber compared with ventricular pacing has been calculated at 62%, and for death 36%. Retrospective studies are, of course, potentially subject to bias, and there may be a tendency to implant cheaper, simpler pacemakers in older, sicker patients, which could explain the apparent difference in outcome. Prospective studies are, therefore, required; results from 3 such studies, in which pacing mode was randomly allocated, have been recently published. These, in general, support the apparent benefit of dual-chamber pacing in patients with sick sinus syndrome, but give equivocal results in patients with heart block. Other trials are in progress, and their results are awaited. Like all good trials, they will, in addition to providing some answers, generate further questions. They should provide the evidence on which cost-effective pacing policies may be based.

Silent myocardial ischemia and microalbuminuria in asymptomatic subjects with non-insulin-dependent diabetes mellitus.

Microalbuminuria is an increase in urinary albumin not detected by conventional dipstick testing and is present in 20% of patients with non-insulin-dependent diabetes mellitus (NIDDM). Mortality in NIDDM patients with microalbuminuria is 60% at 8 years and is mainly due to cardiovascular disease. Because many deaths occur without warning symptoms, we have compared the prevalence and severity of silent myocardial ischemia in asymptomatic NIDDM patients with and without microalbuminuria. We have performed a cross-sectional, case-control study of asymptomatic NIDDM patients attending hospital diabetes clinics. Forty-three patients with microalbuminuria were matched for age, gender, diabetes duration, and smoking status with 43 normoalbuminuric patients. A symptom-limited exercise stress test was performed and reported blind to patient status. The degree of electrocardiographic ST-segment depression, exercise time, work performed, and maximum heart rate with exercise were recorded. Patients with microalbuminuria had a higher prevalence of ischemic response (>1 mm ST depression) (65% vs 40%, p = 0.016), reduced total exercise time (5 vs 7 minutes, p <0.001), reduced work (6 vs 8 METs, p <0.001), and reduced age-predicted maximum heart rate (94% vs 101%, p = 0.004). In multiple logistic regression, albumin excretion rate was shown to be the strongest independent predictor of ischemic response (p = 0.03). Silent myocardial ischemia is common in asymptomatic NIDDM patients but is more common in those with microalbuminuria. In these subjects, the higher prevalence of ischemic response at low workloads suggests a higher probability of future coronary events, and possibly a higher probability of potentially treatable coronary artery disease.