Prolongation of atrio-ventricular node conduction in a rabbit model of ischaemic cardiomyopathy: Role of fibrosis and connexin remodelling.

Conduction abnormalities are frequently associated with cardiac disease, though the mechanisms underlying the commonly associated increases in PQ interval are not known. This study uses a chronic left ventricular (LV) apex myocardial infarction (MI) model in the rabbit to create significant left ventricular dysfunction (LVD) 8weeks post-MI. In vivo studies established that the PQ interval increases by approximately 7ms (10%) with no significant change in average heart rate. Optical mapping of isolated Langendorff perfused rabbit hearts recapitulated this result: time to earliest activation of the LV was increased by 14ms (16%) in the LVD group. Intra-atrial and LV transmural conduction times were not altered in the LVD group. Isolated AVN preparations from the LVD group demonstrated a significantly longer conduction time (by approximately 20ms) between atrial and His electrograms than sham controls across a range of pacing cycle lengths. This difference was accompanied by increased effective refractory period and Wenckebach cycle length, suggesting significantly altered AVN electrophysiology post-MI. The AVN origin of abnormality was further highlighted by optical mapping of the isolated AVN. Immunohistochemistry of AVN preparations revealed increased fibrosis and gap junction protein (connexin43 and 40) remodelling in the AVN of LVD animals compared to sham. A significant increase in myocyte-non-myocyte connexin co-localization was also observed after LVD. These changes may increase the electrotonic load experienced by AVN muscle cells and contribute to slowed conduction velocity within the AVN.

Long-term impact on healthcare resource utilization of statin treatment, and its cost effectiveness in the primary prevention of cardiovascular disease: a record linkage study.

AIMS: To assess the impact on healthcare resource utilization, costs, and quality of life over 15 years from 5 years of statin use in men without a history of myocardial infarction in the West of Scotland Coronary Prevention Study (WOSCOPS). METHODS: Six thousand five hundred and ninety-five participants aged 45-54 years were randomized to 5 years treatment with pravastatin (40 mg) or placebo. Linkage to routinely collected health records extended follow-up for secondary healthcare resource utilization to 15 years. The following new results are reported: cause-specific first and recurrent cardiovascular hospital admissions including myocardial infarction, heart failure, stroke, coronary revascularization and angiography; non-cardiovascular hospitalization; days in hospital; quality-adjusted life years (QALYs); costs of pravastatin treatment, treatment safety monitoring, and hospital admissions. RESULTS: Five years treatment of 1000 patients with pravastatin (40 mg/day) saved the NHS £710 000 (P < 0.001), including the cost of pravastatin and lipid and safety monitoring, and gained 136 QALYs (P = 0.017) over the 15-year period. Benefits per 1000 subjects, attributable to prevention of cardiovascular events, included 163 fewer admissions and a saving of 1836 days in hospital, with fewer admissions for myocardial infarction, stroke, heart failure and coronary revascularization. There was no excess in non-cardiovascular admissions or costs (or in admissions associated with diabetes or its complications) and no evidence of heterogeneity of effect over sub-groups defined by baseline cardiovascular risk. CONCLUSION: Five years' primary prevention treatment of middle-aged men with a statin significantly reduces healthcare resource utilization, is cost saving, and increases QALYs. Treatment of even younger, lower risk individuals is likely to be cost-effective.

N-terminal pro-B-type natriuretic peptide and the prediction of primary cardiovascular events: results from 15-year follow-up of WOSCOPS.

AIMS: To test whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) was independently associated with, and improved the prediction of, cardiovascular disease (CVD) in a primary prevention cohort. METHODS AND RESULTS: In the West of Scotland Coronary Prevention Study (WOSCOPS), a cohort of middle-aged men with hypercholesterolaemia at a moderate risk of CVD, we related the baseline NT-proBNP (geometric mean 28 pg/mL) in 4801 men to the risk of CVD over 15 years during which 1690 experienced CVD events. Taking into account the competing risk of non-CVD death, NT-proBNP was associated with an increased risk of all CVD [HR: 1.17 (95% CI: 1.11-1.23) per standard deviation increase in log NT-proBNP] after adjustment for classical and clinical cardiovascular risk factors plus C-reactive protein. N-terminal pro-B-type natriuretic peptide was more strongly related to the risk of fatal [HR: 1.34 (95% CI: 1.19-1.52)] than non-fatal CVD [HR: 1.17 (95% CI: 1.10-1.24)] (P= 0.022). The addition of NT-proBNP to traditional risk factors improved the C-index (+0.013; P < 0.001). The continuous net reclassification index improved with the addition of NT-proBNP by 19.8% (95% CI: 13.6-25.9%) compared with 9.8% (95% CI: 4.2-15.6%) with the addition of C-reactive protein. N-terminal pro-B-type natriuretic peptide correctly reclassified 14.7% of events, whereas C-reactive protein correctly reclassified 3.4% of events. Results were similar in the 4128 men without evidence of angina, nitrate prescription, minor ECG abnormalities, or prior cerebrovascular disease. CONCLUSION: N-terminal pro-B-type natriuretic peptide predicts CVD events in men without clinical evidence of CHD, angina, or history of stroke, and appears related more strongly to the risk for fatal events. N-terminal pro-B-type natriuretic peptide also provides moderate risk discrimination, in excess of that provided by the measurement of C-reactive protein. Clinical trial registration WOSCOPS was carried out and completed prior to the requirement for clinical trial registration.

Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.

BACKGROUND: Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved. METHODS: We conducted an international, multicenter, randomized, double-blind, prospective trial involving 2776 patients, 50 to 80 years of age, who were undergoing maintenance hemodialysis. We randomly assigned patients to receive rosuvastatin, 10 mg daily, or placebo. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points included death from all causes and individual cardiac and vascular events. RESULTS: After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg per deciliter (2.6 mmol per liter). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P=0.59). Rosuvastatin had no effect on individual components of the primary end point. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.51). CONCLUSIONS: In patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. (ClinicalTrials.gov number, NCT00240331.)

Alternans of action potential duration and amplitude in rabbits with left ventricular dysfunction following myocardial infarction.

T-wave alternans may predict the occurrence of ventricular arrhythmias in patients with left ventricular dysfunction and experimental work has linked discordant repolarization alternans to the induction of re-entry. The aim of this study was to examine the occurrence of transmural repolarization alternans and to investigate the link between alternans and ventricular arrhythmia in rabbits with left ventricular dysfunction following myocardial infarction. Optical mapping was used to record action potentials from the transmural surface of left ventricular wedge preparations from normal and post-infarction hearts during a progressive reduction in pacing cycle length at 30 and 37°C. Data were analyzed using custom software, including spectral analysis. There were no significant differences in baseline transmural electrophysiology between the groups. Post-infarction hearts had a lower threshold for both repolarization alternans (286 vs. 333 bpm, p<0.05) and ventricular arrhythmias (79 vs. 19%, p<0.01) during rapid pacing, which was not accounted for by increased transmural discordant alternans. In VF-prone hearts, alternans in optical action potential amplitude was observed and increased until 2:1 block occurred. The degree of optical action potential amplitude alternans (12.0 ± 7.0 vs. 1.8 ± 0.3, p<0.05), but not APD(90) alternans (1.4 ± 0.6 vs. 1.1 ± 0.1, p>0.05) was associated with VF inducibility during rapid pacing. Post-infarction hearts are more vulnerable to transmural alternans and ventricular arrhythmias at rapid rates. Alternans in optical action potential amplitude was associated with conduction block and VF. The data suggest that changes in optical action potential amplitude may underlie a mechanism for alternans-associated ventricular arrhythmia in left ventricular dysfunction.

Smoke-free legislation and hospitalizations for acute coronary syndrome.

BACKGROUND: Previous studies have suggested a reduction in the total number of hospital admissions for acute coronary syndrome after the enactment of legislation banning smoking in public places. However, it is unknown whether the reduction in admissions involved nonsmokers, smokers, or both. METHODS: Since the end of March 2006, smoking has been prohibited by law in all enclosed public places throughout Scotland. We collected information prospectively on smoking status and exposure to secondhand smoke based on questionnaires and biochemical findings from all patients admitted with acute coronary syndrome to nine Scottish hospitals during the 10-month period preceding the passage of the legislation and during the same period the next year. These hospitals accounted for 64% of admissions for acute coronary syndrome in Scotland, which has a population of 5.1 million. RESULTS: Overall, the number of admissions for acute coronary syndrome decreased from 3235 to 2684--a 17% reduction (95% confidence interval, 16 to 18)--as compared with a 4% reduction in England (which has no such legislation) during the same period and a mean annual decrease of 3% (maximum decrease, 9%) in Scotland during the decade preceding the study. The reduction in the number of admissions was not due to an increase in the number of deaths of patients with acute coronary syndrome who were not admitted to the hospital; this latter number decreased by 6%. There was a 14% reduction in the number of admissions for acute coronary syndrome among smokers, a 19% reduction among former smokers, and a 21% reduction among persons who had never smoked. Persons who had never smoked reported a decrease in the weekly duration of exposure to secondhand smoke (P<0.001 by the chi-square test for trend) that was confirmed by a decrease in their geometric mean concentration of serum cotinine from 0.68 to 0.56 ng per milliliter (P<0.001 by the t-test). CONCLUSIONS: The number of admissions for acute coronary syndrome decreased after the implementation of smoke-free legislation. A total of 67% of the decrease involved nonsmokers. However, fewer admissions among smokers also contributed to the overall reduction.

Fasting plasma glucose in non-diabetic participants and the risk for incident cardiovascular events, diabetes, and mortality: results from WOSCOPS 15-year follow-up.

AIMS: The evidence base for fasting plasma glucose (FPG) in the non-diabetic range as a risk factor for cardiovascular disease (CVD) is inconclusive. We investigated this question in the West of Scotland Coronary Prevention Study (WOSCOPS). METHODS AND RESULTS: In WOSCOPS, we related FPG in 6447 men (mean age 55 years) with hypercholesterolaemia, but no history of CVD or diabetes, to the risk of cardiovascular events and mortality over 14.7 years of follow-up; 2381 non-fatal/fatal cardiovascular events and 1244 deaths occurred. Participants were divided into fifths of baseline FPG, Q1 (< or =4.3 mmol/L) to Q5 (>5.1-6.9 mmol/L). Q2 was designated the referent based on previous studies which have suggested a J-shaped relationship between FPG and CVD. Compared with Q2 (>4.3-4.6 mmol/L), men in Q5 had no elevated risk for cardiovascular events [hazard ratio (HR) 0.95 (0.83-1.08)], or all-cause mortality [HR 0.96 (0.80-1.15)] in fully adjusted analyses despite a significant risk for incident diabetes [HR 22.05 (10.75-45.22)]. After further dividing Q5 into fifths, Q5a-e, individuals in Q5e (FPG 5.8-6.9 mmol/L) were also not at increased risk of cardiovascular events [HR 1.05 (0.82-1.35)] or other endpoints compared with Q2. All results were similar using Q1 as the referent. CONCLUSION: Elevations in FPG in the non-diabetic range were not associated with long-term risk of cardiovascular events in middle-aged men in WOSCOPS. These data suggest that the current FPG cutoff for diagnosing diabetes also appropriately identifies western men at risk of CVD.

Long-term follow-up of the West of Scotland Coronary Prevention Study.

BACKGROUND: The West of Scotland Coronary Prevention Study was a randomized clinical trial comparing pravastatin with placebo in men with hypercholesterolemia who did not have a history of myocardial infarction, with an average follow-up of approximately 5 years. The combined outcome of death from definite coronary heart disease or definite nonfatal myocardial infarction was reduced from 7.9 to 5.5% (P<0.001) in the treatment group. Extended follow-up data were obtained for approximately 10 years after completion of the trial. METHODS: For the survivors of the trial, all deaths, hospitalizations and deaths due to coronary events and stroke, and incident cancers and deaths from cancer were tracked with the use of a national computerized record-linkage system. The results were analyzed with time-to-event analyses and use of Cox proportional-hazards models. RESULTS: Five years after the trial ended, 38.7% of the original statin group and 35.2% of the original placebo group were being treated with a statin. In the period approximately 10 years after completion of the trial, the risk of death from coronary heart disease or nonfatal myocardial infarction was 10.3% in the placebo group and 8.6% in the pravastatin group (P=0.02); over the entire follow-up period, the rate was 15.5% in the placebo group and 11.8% in the pravastatin group (P<0.001). Similar percentage reductions were seen in the combined rate of death from coronary heart disease and hospitalization for coronary events for both periods. The rate of death from cardiovascular causes was reduced (P=0.01), as was the rate of death from any cause (P=0.03), over the entire follow-up period. There were no excess deaths from noncardiovascular causes or excess fatal or incident cancers. CONCLUSIONS: In this analysis, 5 years of treatment with pravastatin was associated with a significant reduction in coronary events for a subsequent 10 years in men with hypercholesterolemia who did not have a history of myocardial infarction.

Effect of activation sequence on transmural patterns of repolarization and action potential duration in rabbit ventricular myocardium.

Although transmural heterogeneity of action potential duration (APD) is established in single cells isolated from different tissue layers, the extent to which it produces transmural gradients of repolarization in electrotonically coupled ventricular myocardium remains controversial. The purpose of this study was to examine the relative contribution of intrinsic cellular gradients of APD and electrotonic influences to transmural repolarization in rabbit ventricular myocardium. Transmural optical mapping was performed in left ventricular wedge preparations from eight rabbits. Transmural patterns of activation, repolarization, and APD were recorded during endocardial and epicardial stimulation. Experimental results were compared with modeled data during variations in electrotonic coupling. A transmural gradient of APD was evident during endocardial stimulation, which reflected differences previously seen in isolated cells, with the longest APD at the endocardium and the shortest at the epicardium (endo: 165 ± 5 vs. epi: 147 ± 4 ms; P < 0.05). During epicardial stimulation, this gradient reversed (epi: 162 ± 4 vs. endo: 148 ± 6 ms; P < 0.05). In both activation sequences, transmural repolarization followed activation and APD shortened along the activation path such that significant transmural gradients of repolarization did not occur. This correlation between transmural activation time and APD was recapitulated in simulations and varied with changes in intercellular coupling, confirming that it is mediated by electrotonic current flow between cells. These data suggest that electrotonic influences are important in determining the transmural repolarization sequence in rabbit ventricular myocardium and that they are sufficient to overcome intrinsic differences in the electrophysiological properties of the cells across the ventricular wall.

Low serum cortisol predicts early death after acute myocardial infarction.

OBJECTIVE: To determine whether low serum cortisol concentrations are associated with adverse prognosis in patients with acute myocardial infarction. Low serum cortisol concentrations have been associated with adverse prognosis in critical illness of diverse etiology. DESIGN: Nested case-control study. SETTING: Prospective cohort study of consecutive patients admitted with acute myocardial infarction to nine Scottish hospitals. PATIENTS: A total of 100 patients who survived 30 days (controls) and 100 patients who died within 30 days (cases). MEASUREMENTS AND MAIN RESULTS: Admission cortisol concentrations were lower in patients who died than those who survived (median, 1189 nmol/L vs. 1355 nmol/L; p < .001). A cortisol concentration in the bottom quartile (<1136 nmol/L) was a strong predictor of death within 30 days and remained so after adjustment for age and cardiac troponin concentration (adjusted odds ratio, 8.78; 95% confidence interval, 3.09-24.96; p < .001). CONCLUSIONS: Patients who mount a lesser cortisol stress response to acute myocardial infarction have a poorer early prognosis.

EHRA Expert Consensus Statement on the management of cardiovascular implantable electronic devices in patients nearing end of life or requesting withdrawal of therapy.

The purpose of this Consensus Statement is to focus on implantable cardioverter-defibrillator (ICD) deactivation in patients with irreversible or terminal illness. This statement summarizes the opinions of the Task Force members, convened by the European Heart Rhythm Association (EHRA) and the Heart Rhythm Society (HRS), based on ethical and legal principles, as well as their own clinical, scientific, and technical experience. It is directed to all healthcare professionals who treat patients with implanted ICDs, nearing end of life, in order to improve the patient dying process. This statement is not intended to recommend or promote device deactivation. Rather, the ultimate judgement regarding this procedure must be made by the patient (or in special conditions by his/her legal representative) after careful communication about the deactivation's consequences, respecting his/her autonomy and clarifying that he/she has a legal and ethical right to refuse it. Obviously, the physician asked to deactivate the ICD and the industry representative asked to assist can conscientiously object to and refuse to perform device deactivation.

Isoprenaline increases the slopes of restitution trajectory in the conscious rabbit with ischemic heart failure.

Roughly speaking, restitution is the dependence of recovery time of cardiac electrical activity on heart rate. Increased restitution slope is theorized to be predictive of sudden death after heart injury such as from coronary artery occlusion (ischemia). Adrenaline analogs are known to increase restitution slope in normal hearts, but their effects in failing hearts are unknown. Twenty-six rabbits underwent coronary ligation (n = 15) or sham surgery (n = 11) and implantation of a lead in the heart for recording electrocardiograms. Eight weeks later, unanesthetized rabbits were given 0.25-2.0 ml of 1 µmol/L isoprenaline intravenously, which increased heart rate. Heart rate was quantified by time between QRS peaks (RR) and heart activity duration by R to T peak time (QTp). Ligated rabbits (n = 6) had lower ejection fraction than sham rabbits (n = 7, p < 0.0001) indicative of heart failure, but similar baseline RR (269 ± 15 vs 292 ± 23 ms, p = 0.07), QTp (104 ± 17 vs 91 ± 9 ms, p = 0.1), and isoprenaline-induced minimum RR (204 ± 11 vs 208 ± 6 ms, p = 0.4). The trajectory of QTp vs TQ plots displayed hysteresis and regions of negative slope. The slope of the positive slope region was >1 in ligated rabbits (1.27 ± 0.66) and <1 in sham rabbits (0.35 ± 0.14, p = 0.004). The absolute value of the negative slope was greater in ligated rabbits (- 0.81 ± 0.52 vs - 0.35 ± 0.14, p = 0.04). Isoprenaline increased heart rate and slopes of restitution trajectory in failing hearts. The dynamics of restitution trajectory may hold clues for sudden death in heart failure patients.

Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

BACKGROUND: Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke. METHODS AND FINDINGS: In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), baseline inflammatory markers in up to 5,680 men and women aged 70-82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672]), fatal CVD (n = 190), death from other CV causes (n = 38), and non-CVD mortality (n = 300), over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis) more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44-2.12) than with risk of nonfatal CVD (1.17, 95% CI 1.04-1.31), in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction). The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001) improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20). CONCLUSIONS: In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.

Paced ventricular electrogram fractionation predicts sudden cardiac death in hypertrophic cardiomyopathy.

AIMS: Paced electrogram fractionation analysis (PEFA) has been assessed for the prediction of sudden cardiac death (SCD) in a large-scale, prospective study of patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: We determined the positive predictive value (PPV) of PEFA in relation to other risk factors for SCD and outcomes in 179 patients with HCM and no prior history of cardiac arrest. Patients were followed over a mean 4.3 years (range: 1.1-6.3 years). Thirteen patients had SCD-equivalent events: four of these patients died suddenly, three were resuscitated from ventricular fibrillation (VF), and six had implantable cardioverter-defibrillator (ICD) discharges in response to VF. PEFA identified nine of these patients and another 14 non-VF patients yielding a censored PPV of between 0.19 and 0.59 that was greater than the PPV that was the formal stopping point of the trial (0.18). Eighty per cent of patients were followed for 4 years or more. The PPV for the identification of SCD in this group was 0.38 (0.17-0.59). The use of two or more conventional markers to predict SCD identified five patients with SCD-equivalent events in the 4-year follow-up group and 42 other patients without events yielding a PPV of 0.106 (confidence limits 0.02-0.15). CONCLUSION: PEFA identifies HCM patients at risk of SCD with greater accuracy than non-invasive techniques and may have an important role in determining indications for ICD prescription.

Paroxysmal bidirectional ventricular tachycardia with tachycardiomyopathy in a pregnant woman.

Palpitations in pregnancy are not an uncommon complaint. We present a case of palpitations in the third trimester related to bidirectional ventricular tachycardia with evidence, of left ventricular systolic dysfunction. The case was successfully managed with flecainide therapy and urgent elective caesarean section. The rhythm stabilised to sinus rhythm and left ventricular systolic function normalised. We discuss the possible underlying diagnosis of catecholaminergic polymorphic ventricular tachycardia with resultant tachycardiomyopathy. A literature review of bidirectional ventricular tachycardia is presented. This is the first reported case of bidirectional VT producing LV systolic dysfunction, which normalised following stabilisation of rhythm. The complex issues of management of this case in particular with regard to the pregnancy are discussed.

The link between repolarisation alternans and ventricular arrhythmia: does the cellular phenomenon extend to the clinical problem?

T-wave alternans is considered a potentially useful clinical marker for the risk of ventricular arrhythmia in patients with heart disease. Cellular repolarisation alternans is thought to underlie T-wave alternans, and moreover, to cause re-entrant ventricular arrhythmia. This review examines the experimental and clinical evidence linking repolarisation alternans and T-wave alternans with the occurrence of ventricular arrhythmia. Repolarisation alternans, manifest as alternating changes in action potential duration, is observed in isolated ventricular cardiomyocytes and in multicellular preparations. Its underlying causes are discussed particularly with respect to the role of intracellular Ca(2+). The repolarisation alternans observed at the single cell level is compared to the alternating behaviour observed in isolated multicellular preparations including the perfused ventricular wedge and Langendorff perfused heart. The evidence concerning spatial differences in repolarisation alternans is considered, particularly the situation where adjacent regions of myocardium exhibit repolarisation alternans of different phases. This extreme behaviour, known as discordant alternans, is thought to produce marked gradients of repolarisation that can precipitate unidirectional block and re-entrant ventricular arrhythmias. Finally, the difficulties in extrapolating between experimental models of alternans and arrhythmias and the clinical manifestation are discussed. The areas where experimental evidence is weak are highlighted, and areas for future research are outlined.

C-reactive protein and prediction of coronary heart disease and global vascular events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).

BACKGROUND: The role of C-reactive protein (CRP) in predicting vascular events and response to statin therapy remains uncertain. Additional large prospective studies are required. METHODS AND RESULTS: Baseline CRP was related to risk over 3.2 years for primary a combined end point (definite or suspected death from coronary heart disease, nonfatal myocardial infarction, and fatal or nonfatal stroke; n=865 events) and secondary (coronary heart disease events or stroke alone) and tertiary (stroke plus transient ischemic attack) end points in the Prospective Study of Pravastatin in the Elderly at Risk (n=5804 men and women; age, 70 to 82 years). CRP levels were higher in subjects who had a subsequent primary end-point event compared with those who did not (geometric mean; 3.64 mg/L [SD, 3.08 mg/L] versus 3.01 mg/L [SD, 3.05 mg/L]; P<0.0001). CRP correlated positively with body mass index and smoking status and negatively with high-density lipoprotein cholesterol. The unadjusted hazard ratio for the primary end point was 1.48 (95% CI, 1.26 to 1.74) in a comparison of top and bottom thirds for CRP, falling to 1.36 (95% CI, 1.15 to 1.61) with adjustment for established predictors and body mass index. Similar results were obtained for other end points or when results were examined separately by history of vascular disease. However, baseline CRP added minimally to risk prediction beyond conventional predictors and did not relate to the magnitude of pravastatin benefit. CONCLUSIONS: Elevated CRP minimally enhances cardiovascular disease prediction beyond established vascular risk factors and does not predict response to statin therapy in elderly subjects at risk. These data suggest that CRP has limited clinical value in cardiovascular disease risk stratification or predicting response to statin therapy in elderly people.

Serial metabolic measurements and conversion to type 2 diabetes in the west of Scotland coronary prevention study: specific elevations in alanine aminotransferase and triglycerides suggest hepatic fat accumulation as a potential contributing factor.

To examine metabolic changes (lipids, liver enzymes, blood pressure, and weight) potentially associated with conversion to diabetes, we analyzed serial glucose and other metabolic measures obtained every 6 months within the West of Scotland Coronary Prevention Study trial. Changes in parameters for 86 men who converted to new-onset diabetes ("converters": two consecutive glucose levels > or =7 mmol/l) were compared with 860 "nonconverters" matched for age and treatment allocation. Eighteen months before the diagnosis, converters to diabetes had elevated (P < 0.01) fasting glucose, weight, triglyceride, alanine aminotransferase (ALT), blood pressure, and white cell count and lower HDL cholesterol compared with nonconverters. The mean (SD) increase in fasting glucose over 18 months in converters was 1.80 (1.52) mmol/l, compared with 0.10 (0.57) in nonconverters. Of parameters measured, only ALT (P = 0.0005) and triglyceride (P = 0.030) increased significantly more over the 18 months in converters compared with nonconverters, but neither parameter increased significantly in nonconverters with high baseline glucose concentrations (>6.1 mmol/l). Finally, only sustained increases in ALT predicted a higher risk for diabetes. We conclude that a relatively rapid rise in fasting glucose levels is frequent in converters to diabetes and that associated increases over time in ALT and potentially triglyceride suggest hepatic fat accumulation as a contributing factor for conversion to diabetes in men at risk.

Heterogeneity of ventricular fibrillation dominant frequency during global ischemia in isolated rabbit hearts.

INTRODUCTION: Ventricular fibrillation (VF) studies show that ECG-dominant frequency (DF) decreases as ischemia develops. This study investigates the contribution of the principle ischemic metabolic components to this decline. METHODS AND RESULTS: Rabbit hearts were Langendorff-perfused at 40 mL/min with Tyrode's solution and loaded with RH237. Epicardial optical action potentials were recorded with a photodiode array (256 sites, 15 x 15 mm). After 60 seconds of VF (induced by burst pacing), global ischemia was produced by low flow (6 mL/min), or the solution changed to impose hypoxia (95% N2/5% CO2), low pH(o) (6.7, 80% O2/20% CO2), or raised [K+](o) (8 mM). DF of the optical signals was determined at each site. Conduction velocity (CV), action potential duration (APD90), effective refractory period (ERP), activation threshold, dV/dt(max), and membrane potential were measured in separate experiments during ventricular pacing. During VF, ischemia decreased DF in the left ventricle (LV) (to [58 +/- 6]%, P < 0.001), but not the right (RV) ([93 +/- 5]%). Raised [K+](o) reproduced this DF pattern (LV: [67 +/- 12]%, P < 0.001; RV: [95 +/- 9]%). LV DF remained elevated in hypoxia or low pH(o). During ventricular pacing, ischemia decreased CV in LV but not RV. Raised [K+](o) did not change CV in either ventricle. Ischemia and raised [K+](o) shortened APD90 without altering ERP. LV activation threshold increased in both ischemia and raised [K+](o) and was associated with diastolic depolarization and decreased dV/dt(max). CONCLUSIONS: These results suggest that during VF, decreased ECG DF in global ischemia is largely due to elevated [K+](o) affecting the activation thresholds in the LV rather than RV.

Mapping of epicardial activation in a rabbit model of chronic myocardial infarction:.

INTRODUCTION: This study examines the consequences of a large transmural apical infarct on the epicardial electrical activity in isolated rabbit hearts. METHODS AND RESULTS: Hearts were isolated 8 weeks after coronary artery ligation. Membrane voltage from the epicardial surface of the left ventricle (LV) including the infarct was monitored using the voltage sensitive dye RH237. Optical action potentials were detected from the epicardial surface of the infarct; the signal amplitude was approximately 20% of those in the noninfarcted zone (NZ). Epicardial activation mapping of the LV free wall showed that during right atrial (RA) pacing, the activation sequence was not significantly different between infarcted and sham-operated groups. However, direct stimulation of the epicardium in the NZ revealed an area of slow conduction velocity (CV approximately 5 cm/s(-1), approximately 10% of normal values) at the margin of the infarct zone (IZ). Within the IZ, CV was approximately 50% of normal. A prominent endocardial rim of myocardium in the infarct was not the source of epicardial optical signals because chemical ablation of the endocardium did not affect the epicardial activation pattern. CONCLUSION: Therefore, remnant groups of myocytes in the mid-wall and epicardium of the infarct scar support normal electrical activation during RA pacing. Areas of delayed conduction emerge only on epicardial stimulation.