Stuart D. Pringle

The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease

Objective To determine whether aspirin and antioxidant therapy, combined or alone, are more effective than placebo in reducing the development of cardiovascular events in patients with diabetes mellitus and asymptomatic peripheral arterial disease. Design Multicentre, randomised, double blind, 2×2 factorial, placebo controlled trial. Setting 16 hospital centres in Scotland, supported by 188 primary care groups. Participants 1276 adults aged 40 or more with type 1 or type 2 diabetes and an ankle brachial pressure index of 0.99 or less but no symptomatic cardiovascular disease. Interventions Daily, 100 mg aspirin tablet plus antioxidant capsule (n=320), aspirin tablet plus placebo capsule (n=318), placebo tablet plus antioxidant capsule (n=320), or placebo tablet plus placebo capsule (n=318). Main outcome measures Two hierarchical composite primary end points of death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or amputation above the ankle for critical limb ischaemia; and death from coronary heart disease or stroke. Results No evidence was found of any interaction between aspirin and antioxidant. Overall, 116 of 638 primary events occurred in the aspirin groups compared with 117 of 638 in the no aspirin groups (18.2% v 18.3%): hazard ratio 0.98 (95% confidence interval 0.76 to 1.26). Forty three deaths from coronary heart disease or stroke occurred in the aspirin groups compared with 35 in the no aspirin groups (6.7% v 5.5%): 1.23 (0.79 to 1.93). Among the antioxidant groups 117 of 640 (18.3%) primary events occurred compared with 116 of 636 (18.2%) in the no antioxidant groups (1.03, 0.79 to 1.33). Forty two (6.6%) deaths from coronary heart disease or stroke occurred in the antioxidant groups compared with 36 (5.7%) in the no antioxidant groups (1.21, 0.78 to 1.89). Conclusion This trial does not provide evidence to support the use of aspirin or antioxidants in primary prevention of cardiovascular events and mortality in the population with diabetes studied. Trial registration Current Controlled Trials ISRCTN53295293.

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.

Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure

OBJECTIVES The study was designed to comprehensively evaluate the circadian effects of aldosterone blockade on autonomic tone and QT dispersion in chronic heart failure (CHF). BACKGROUND Spironolactone therapy given in addition to angiotensin-converting enzyme inhibitors improved survival in CHF, but the mechanism of its benefit is uncertain. Experimental evidence suggests that aldosterone may have detrimental effects on the autonomic nervous system, especially during the morning hours. METHODS Twenty-eight patients with New York Heart Association class II to IV CHF received spironolactone 50 mg daily and placebo for four weeks each in a double-blind crossover fashion. After each treatment phase, a full circadian assessment was undertaken of spironolactones autonomic effects. The assessment included monitoring heart rate, QT dispersion, continuous Holter recordings, heart rate variability (HRV) and norepinephrine kinetics. RESULTS Spironolactone significantly reduced all indices of QT dispersion. The reductions in QTcmax, QTd and QTcd were greatest at 6 AM. In addition, spironolactone had favorable autonomic effects, which were limited to the morning (6-10 AM), including heart rate reduction and an improvement in HRV. CONCLUSIONS Spironolactone reduced heart rate and improved HRV and QT dispersion in CHF. Its effects were particularly prominent during the morning hours.

Impact of Renin-Angiotensin System Blockade Therapy on Outcome in Aortic Stenosis

OBJECTIVES The purpose of this study was to investigate the impact of renin-angiotensin system blockade therapy on outcomes in aortic stenosis (AS). BACKGROUND Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are perceived to be relatively contraindicated in AS. However, inhibitors of the renin-angiotensin system may be beneficial in AS through their cardioprotective and beneficial effects on left ventricular remodeling. METHODS The Health Informatics dispensed prescribing, morbidity, and mortality database for the population of Tayside, Scotland, was linked through a unique patient identifier to the Tayside echocardiography database (>110,000 scans). Patients with a diagnosis of AS from 1993 to 2008 were identified. Cox regression model (adjusted for confounding variables) and propensity score analysis were used to assess the impact of ACEIs or ARBs on all-cause mortality and cardiovascular (CV) events (CV death or hospitalizations). RESULTS A total of 2,117 patients with AS (mean age 73 ± 12 years, 46% men) were identified and 699 (33%) were on ACEI or ARB therapy. Over a mean follow-up of 4.2 years, there were 1,087 (51%) all-cause deaths and 1,018 (48%) CV events. Those treated with ACEIs or ARBs had a significantly lower all-cause mortality with an adjusted hazard ratio of 0.76 (95% confidence interval: 0.62 to 0.92, p < 0.0001) and fewer CV events with an adjusted hazard ratio of 0.77 (95% confidence interval: 0.65 to 0.92, p < 0.0001). The outcome benefits of ACEIs/ARBs were further supported by propensity score analysis. CONCLUSIONS This large observational study suggests that ACEI/ARB therapy is associated with an improved survival and a lower risk of CV events in patients with AS.

Cross sectional study of contribution of clinical assessment and simple cardiac investigations to diagnosis of left ventricular systolic dysfunction in patients admitted with acute dyspnoea

Abstract Objective: To assess the comparative contribution of clinical assessment, electrocardiography, and chest radiography to the diagnosis of left ventricular systolic dysfunction in patients admitted to a general medical ward with acute dyspnoea. Design: Prospective cross sectional study. Setting: Acute medical admissions ward of a teaching hospital. Subjects: 71 randomly selected patients admitted with acute dyspnoea. Main outcome measures: Sensitivity and specificity of each investigation and logistic regression analysis of each variable in identifying left ventricular systolic dysfunction. Results: Clinical assessment in this cohort of patients with severe dyspnoea was generally sensitive (sensitivity 81%). Patients were divided into three groups on the basis of clinical assessment. In the first group (37 patients) the diagnosis of systolic dysfunction was clear, in the second (22) it was in doubt, and in the third (12) it was unlikely. The sensitivity of clinical assessment in identifying left ventricular systolic dysfunction was 81% and the specificity was 47%. The specificity of diagnosis was improved by electrocardiography (69%) and chest radiography (92%). Logistic regression analysis showed that isolated pulmonary crepitations were a comparatively poor predictor of left ventricular systolic dysfunction (2=10.215, P=0.0014) but that a full clinical examination had reasonable predictive value (2=24.82, P<0.00001). The combination of clinical assessment and chest radiography improved the accuracy of diagnosis (2=28.08, P<0.00001), as did the combination of clinical assessment and electrocardiography (2=32.41, P<0.00001). Conclusion: Clinical assessment in patients admitted with acute dyspnoea is comparatively accurate. Patients with abnormal results on chest radiography, electrocardiography, and clinical examination have a high likelihood of having left ventricular systolic dysfunction. Echocardiography contributes little more to the diagnosis in these patients and may be more efficiently directed towards patients in whom the diagnosis is still in doubt after clinical assessment, chest radiography, and electrocardiography. Key messages The availability of echocardiography is limited for patients admitted to hospital with acute dyspnoea The presence of isolated lung crepitations is a poor predictor of left ventricular systolic dysfunction Full clinical assessment is sensitive in detecting left ventricular systolic dysfunction, with specificity being added by either chest radiography or electrocardiography Echocardiography should be reserved for cases with the most diagnostic doubt

Reference values and reproducibility of Doppler echocardiography in the assessment of the tricuspid valve and right ventricular diastolic function in normal subjects

The Doppler echocardiographic indexes of the tricuspid and mitral valves were assessed in 74 normal subjects (35 women and 39 men, mean age 45 years). A reproducibility study was also performed to examine the various sources of technical and biological variability. There were significantly higher peak early and late flow velocities across the mitral valve than across the tricuspid valve (0.67 +/- 0.13 and 0.47 +/- 0.12 vs 0.51 +/- 0.08 and 0.35 +/- 0.09 m.s-1, respectively; all p less than 0.0001). There was no significant difference between the early:late (E:A) velocity ratios of the 2 valves (1.65 +/- 0.73 vs 1.75 +/- 0.67, p less than 0.01). There was a steeper mitral early deceleration slope (-3.59 +/- 1.07 vs -2.95 +/- 0.91 m.s-2) but no significant difference in pressure half-times across the 2 valves (47 +/- 7 vs 51 +/- 12 ms, p less than 0.1). No influence of gender or body surface area could be demonstrated. There was a weak but significant relation between mitral peak early, peak atrial velocity and E:A ratio and age (r = -0.39, p less than 0.001, r = 0.23, p less than 0.01, and r = -0.245, p less than 0.01, respectively). There was no significant correlation between any of the tricuspid flow parameters and age. Respiration caused pronounced variability in the tricuspid Doppler indexes and all tricuspid flows were sampled and analyzed only during inspiration. The intra- and interobserver variabilities were small for all of the Doppler indexes measured, but the day-to-day variability was quite significant especially for the pressure half-time, deceleration and acceleration slope values.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathophysiologic assessment of left ventricular hypertrophy and strain in asymptomatic patients with essential hypertension

To investigate the significance of the electrocardiographic (ECG) pattern of left ventricular hypertrophy and strain, two groups of asymptomatic patients with essential hypertension were compared. The patients were similar in terms of age, smoking habit, serum cholesterol and blood pressure levels, but differed in the presence (Group I, n = 23) or absence (Group II, n = 23) of the ECG pattern of left ventricular hypertrophy and strain. Group I patients had significantly more episodes of exercise-induced ST segment depression (14 versus 4, p less than 0.05) and reversible thallium perfusion abnormalities (11 of 23 versus 3 of 23, p less than 0.05) despite similar exercise capacity and absence of chest pain. Nonsustained ventricular tachycardia was detected on 24 h ambulatory ECG monitoring in two patients in Group I, but no patient in Group II. Coronary arteriography performed in 20 Group I patients demonstrated significant coronary artery disease in 8 patients. This study has shown that there is a subgroup of hypertensive patients with ECG left ventricular hypertrophy and strain who have covert coronary artery disease. This can be detected by thallium perfusion scintigraphy, and may contribute to the increased risk known to be associated with this ECG abnormality.

Is Glutamine beneficial in ischemic heart disease

OBJECTIVE Glutamine enhances recovery from acute normothermic ischemia in isolated rat heart by a dose-dependent effect (Khogali et al. J Mol Cell Cardiol 1998;30:819). We compared the cardioprotective effects of equimolar concentrations of glutamine, glutamate, and aspartate in isolated rat heart. We also explored the potential cardioprotective effects of glutamine in patients with chronic stable angina. METHODS The isolated perfused working rat heart was subjected to ischemia, followed by reperfusion with or without an amino acid (2.5 mM). Patients with chronic stable angina received a single oral dose of glutamine (80 mg/kg) or placebo in a double-blind, random fashion 40 min before a standard Bruce exercise test. RESULTS Postischemic reperfusion of isolated rat heart with glutamine (but not with glutamate or aspartate) resulted in full recovery of cardiac output. Only glutamine prevented the decrease in the myocardial ratio between adenosine triphosphate to adenosine diphosphate and significantly enhanced the myocardial ratio of reduced to oxidized glutathione. A single oral dose of glutamine given to patients with chronic stable angina significantly increased plasma glutamine concentration from 419 to 649 microM and delayed time to onset of more than 1.0 mm of ST segment depression on the ECG by 38 s. CONCLUSION Glutamine may be cardioprotective in patients with coronary heart disease.

Relation of QT interval dispersion to the number of different cardiac abnormalities in diabetes mellitus

Three studies have clearly shown that a prolonged QT dispersion (QTD) is the best predictor of cardiac death in patients with type 2 diabetes mellitus (DM). This was originally believed to be because QTD identified electrical inhomogeneity, but recent data suggests that this is unlikely. The alternative possibility is that QTD is a convenient identifier of hidden but lethal cardiac abnormalities. We explored whether the latter possibility is true by examining exactly what spectrum of cardiac abnormalities, if any, are over-represented in diabetics with a prolonged QTD. Two hundred nineteen patients with type 2 DM who had been first diagnosed with DM 3 to 6 years previously underwent intensive cardiac examinations. Patients with prolonged QTD had a significantly increased incidence of myocardial ischemia and left ventricular (LV) hypertrophy, and to a lesser extent, autonomic dysfunction. The main independent determinant of a prolonged QTD was ischemia, as seen on both ambulatory ST-segment monitoring (p <0.001) and Duke score on treadmill testing (p <0.001). It was also observed that QTD increased progressively as the number of different cardiac abnormalities increased (p <0.001). These studies suggest that QTD is a useful, general prescreening test to select diabetics for more detailed cardiac examinations (especially for ischemia and LV hypertrophy), and that if cardiac examinations were targeted by way of QTD screening, then a high incidence of hidden but treatable cardiac abnormalities could be found.

Sudden cardiac death, ventricular arrhythmias and hypertensive left ventricular hypertrophy

Objective: To evaluate the relationship between sudden cardiac death, ventricular arrhythmias and left ventricular hypertrophy in patients with hypertension. Data identification: Epidemiological studies assessing the importance of left ventricular hypertrophy as a risk factor for sudden cardiac death, studies assessing the prevalence of arrhythmias in left ventricular hypertrophy and studies assessing whether there is an electrophysiological substrate in the hypertrophied myocardium for ventricular dysrhythmias. Results of data analysis: Current evidence indicates that left ventricular hypertrophy is a risk factor for sudden cardiac death and that ventricular arrhythmias are more prevalent in hypertensive patients with than in those without left ventricular hypertrophy. However, there is a lack of evidence that these dysrhythmias are important as an underlying mechanism for sudden cardiac death, and there is no clear evidence that the hypertrophied myocardium is, itself, an arrhythmogenic substrate for malignant ventricular dysrthyhmias. One possible mechanism for sudden cardiac death is myocardial ischaemia, either as a consequence of asssociated coronary disease or due to left ventricular hypertrophy, but this remains unproved. Conclusions: There is currently no evidence that the ventricular ectopic activity seen in patients with hypertensive left ventricular hypertrophy is a marker for sudden cardiac death. Clarification of the mechanisms involved in sudden cardiac death will help in selecting appropriate preventive and therapeutic strategies for these patients.