Peter W Macfarlane

Publications of Peter W Macfarlane

• Subclinical Thyroid Dysfunction and the Risk of Heart Failure in Older Persons at High Cardiovascular Risk.

  Authors: David Nanchen, Jacobijn Gussekloo, Rudi G J Westendorp, David J Stott, J Wouter Jukema, Stella Trompet, Ian Ford, Paul Welsh, Naveed Sattar, Peter W Macfarlane, Simon P Mooijaart, Nicolas Rodondi, Anton J M de Craen

  The Journal of clinical endocrinology and metabolism. 03/2012; 97(3):852-861.

  Context: Subclinical thyroid dysfunction is common in older people. However, its clinical importance is uncertain. Objective: Our objective was to determine the extent to which subclinicalContext: Subclinical thyroid dysfunction is common in older people. However, its clinical importance is uncertain. Objective: Our objective was to determine the extent to which subclinical hyperthyroidism and hypothyroidism influence the risk of heart failure and cardiovascular diseases in older people. Setting and Design: The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) is an prospective cohort study. Patients: Patients included men and women aged 70-82 yr (n = 5316) with known cardiovascular risk factors or previous cardiovascular disease. Main Outcome Measures: Incidence rate of heart failure hospitalization, atrial fibrillation, and cardiovascular events and mortality according to baseline thyroid status were evaluated. Euthyroid participants (TSH =0.45-4.5 mIU/liter) were compared with those with subclinical hyperthyroidism (TSH <0.45 mIU/liter) and those with subclinical hypothyroidism (TSH ≥4.5 mIU/liter, both with normal free T(4)). Results: Subclinical hyperthyroidism was present in 71 participants and subclinical hypothyroidism in 199 participants. Over 3.2 yr follow-up, the rate of heart failure was higher for subclinical hyperthyroidism compared with euthyroidism [age- and sex-adjusted hazard ratio (HR) = 2.93, 95% confidence interval (CI) = 1.37-6.24, P = 0.005; multivariate-adjusted HR = 3.27, 95% CI = 1.52-7.02, P = 0.002). Subclinical hypothyroidism (only at threshold >10 mIU/liter) was associated with heart failure (age- and sex-adjusted HR = 3.01, 95% CI = 1.12-8.11, P = 0.029; multivariate HR = 2.28, 95% CI = 0.84-6.23). There were no strong evidence of an association between subclinical thyroid dysfunction and cardiovascular events or mortality, except in those with TSH below 0.1 or over 10 mIU/liter and not taking pravastatin. Conclusion: Older people at high cardiovascular risk with low or very high TSH along with normal free T(4) appear at increased risk of incident heart failure.

• Reply to the letter by hayashi et Al.

  Authors: Wibke Reinhard, Bernhard M Kaess, Radoslaw Debiec, Christopher P Nelson, Klaus Stark, Martin D Tobin, Peter W Macfarlane, Maciej Tomaszewski, Nilesh J Samani, Christian Hengstenberg

  Circulation. Cardiovascular genetics. 10/2011; 4(5):e21.

• Determinants of a reduced heart rate variability in chronic atrial fibrillation.

  Authors: Maciej Sosnowski, Peter W Macfarlane, Michał Tendera

  Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 10/2011; 16(4):321-6.

  We aimed to evaluate whether clinical factors, which influence heart rate variability (HRV) in the presence of undisturbed sinus rhythm, have any associations with HRV in patients with permanentWe aimed to evaluate whether clinical factors, which influence heart rate variability (HRV) in the presence of undisturbed sinus rhythm, have any associations with HRV in patients with permanent atrial fibrillation (AF). One hundred ninety-seven consecutive patients with permanent AF were included (122 males, 75 females, aged 64 ± 11 years, range 25-85). In each patient a 24-hour electrocardiographic recording was performed and an HRV fraction (HRVF)-the index based on scatter plot numerical processing-was calculated. Additionally, standard HRV measures were analyzed. Reduced HRVF was defined as its value lower than lower normal limit. Demographic and clinical factors were examined for their association with a reduced HRVF by means of a univariate and multivariate logistic regression analysis. The reduced HRVF was associated with advanced age, clinical diagnosis of a previous MI or dilated cardiomyopathy, presence of diabetes, depressed left ventricular function, NYHA class > II, treatment regimen, use of digoxin, diuretics or antiarrhythmic agents, nonuse of beta-blockers, and increased heart rate. The independent determinants that sustained after multivariate analysis were: heart rate (per 10 bpm increase, odds ratio 2.77 [1.88-4.07]), age (per 5 years increase 1.43 [1.1-1.85]), depressed left ventricular EF (<30% vs higher 2.26 [1.19-4.31]), and presence of diabetes (3.45 [1.1-10.85]). The HRVF correlated moderately with standard HRV measures. This index showed also the strongest correlation with left ventricular ejection fraction. We concluded that advanced age, left ventricular systolic dysfunction, increased heart rate, and presence of diabetes are cofactors of a reduced HRV in AF patients. Thus, the determinants of heart rate variability in the presence of atrial fibrillation are the same as those in sinus rhythm.

• Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy.

  Authors: Sonia Shah, Christopher P Nelson, Tom R Gaunt, Pim van der Harst, Timothy Barnes, Peter S Braund, Debbie A Lawlor, Juan-Pablo Casas, Sandosh Padmanabhan, Fotios Drenos [......] Rudolf A de Boer, Gerjan Navis, Wiek H van Gilst, Bongani M Mayosi, John R Thompson, Meena Kumari, Peter W MacFarlane, Ian N M Day, Aroon D Hingorani, Nilesh J Samani

  Circulation. Cardiovascular genetics. 09/2011; 4(6):626-35.

  Presence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability ofPresence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of 4 commonly measured indices of ECG-LVH. We calculated the Sokolow-Lyon index, Cornell product, 12-lead QRS voltage sum, and 12-lead QRS voltage product in 10 256 individuals from 3 population-based cohorts and typed their DNA using a customized gene array (the Illumina HumanCVD BeadChip 50K array), containing 49 094 genetic variants in ≈2100 genes of cardiovascular relevance. We followed-up promising associations in 11 777 additional individuals. We identified and replicated 4 loci associated with ECG-LVH indices: 3p22.2 (SCN5A, rs6797133, P=1.22 × 10(-7)) with Cornell product and 12q13.3 (PTGES3, rs2290893, P=3.74 × 10(-8)), 15q25.2 (NMB, rs2292462, P=3.23 × 10(-9)), and 15q26.3 (IGF1R, rs4966014, P=1.26 × 10(-7)) with the 12-lead QRS voltage sum. The odds ratio of being in the top decile for the 12-lead QRS voltage sum for those carrying 6 trait-raising alleles at the 12q13.3, 15q25.2, and 15q26.3 loci versus those carrying 0 to 1 alleles was 1.60 (95% CI: 1.20 to 2.29). Lead single-nucleotide polymorphisms at the 12q13.3 and 15q25.2 loci showed significant expression quantitative trait loci effects in monocytes. These findings provide novel insights into the genetic determination of ECG-LVH. The findings could help to improve our understanding of the mechanisms determining this prognostically important trait.

• The incidence and risk factors for new onset atrial fibrillation in the PROSPER study.

  Authors: Peter W Macfarlane, Heather Murray, Naveed Sattar, David J Stott, Ian Ford, Brendan Buckley, J Wouter Jukema, Rudi G J Westendorp, James Shepherd

  Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 02/2011; 13(5):634-9.

  Atrial fibrillation/flutter (AF) is the most common arrhythmia in older people. It associates with reduced exercise capacity, increased risk of stroke, and mortality. We aimed to determineAtrial fibrillation/flutter (AF) is the most common arrhythmia in older people. It associates with reduced exercise capacity, increased risk of stroke, and mortality. We aimed to determine retrospectively whether pravastatin reduces the incidence of AF and whether any electrocardiographic measures or clinical conditions might be risk factors for its development. The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) was a randomized, double-blind controlled trial that recruited 5804 individuals aged 70-82 years with a history of, or risk factors for, vascular disease. A total of 2891 were allocated to pravastatin and 2913 to placebo; mean follow-up was 3.2 years. Electrocardiograms (ECGs), which were recorded at baseline, annually thereafter, and at run-out, were processed by computer and reviewed manually. In all, 264 of 2912 (9.1%) of the placebo group and 283 of 2888 (9.8%) of the pravastatin-treated group developed AF [hazard ratio 1.08 (0.92,1.28), P= 0.35)]. Multivariate analysis showed that PR and QTc intervals, age, left ventricular hypertrophy, and ST-T abnormalities were related to development of AF after adjustment for many variables including alcohol consumption, which itself was univariately predictive of developing AF. Previous myocardial infarction on the ECG was not a risk factor. A history of vascular disease was strongly linked with developing AF but not diabetes and hypertension. Pravastatin does not reduce the incidence of AF in older people at risk of vascular disease, at least in the short-medium term. Risk factors for AF include older age, prolongation of PR or QTc intervals, left ventricular hypertrophy, and ST-T abnormalities on the ECG.

• Relationship between R-R interval variation and left ventricular function in sinus rhythm and atrial fibrillation as estimated by means of heart rate variability fraction.

  Authors: Maciej Sosnowski, Barbara Korzeniowska, Peter W Macfarlane, Michał Tendera

  Cardiology journal. 01/2011; 18(5):538-45.

  Reduced heart rate variability (HRV) is associated with a poor outcome in patients with sinus rhythm (SR) or atrial fibrillation (AF). However, cut-off points for HRV measures differ between SR andReduced heart rate variability (HRV) is associated with a poor outcome in patients with sinus rhythm (SR) or atrial fibrillation (AF). However, cut-off points for HRV measures differ between SR and AF. We hypothesized that a global index of 24-hour HRV based on evaluation of scatterplot would describe HRV irrespective of cardiac rhythm. 407 patients with ischemic heart disease (317 male, 90 female, mean age 57 ± 9 years) were studied. 331 patients had SR and 76 patients had AF. 24-hour ECGs were recorded, and standard HRV indices were calculated. Scatterplots was used to determine the HRV fraction (HRVF, %). HRV measures were compared in respect to left ventricular ejection fraction (LVEF £ 35% or 〉 35%). Standard HRV measures were higher in AF-patients despite the mean RR interval was lower. In patients with LVEF £ 35%, standard HRV indices were lower in SR group, in AF group only SDNN and RMSSD were reduced. The HRVF was comparably reduced (SR 39.3 ± 15.3%, AF 37.3 ± 17.9%). In patients with LVEF 〉 35%, HRVF did not differ between SR (47.2 ± ± 10.5%) and AF (46.1 ± 12.1%). The HRVF correlated with SDNN and SDANN (~0.85) in SR. Correlations were weaker in AF (~0.6). Standard HRV indices and HRVF showed similar relations with LVEF, but only in AF at the same range. The HRV fraction allows for HRV evaluation irrespective of cardiac rhythm. The index elicited a similar dependence of HRV on left ventricular function in SR and AF.

• Heritability of early repolarization: a population-based study.

  Authors: Wibke Reinhard, Bernhard M Kaess, Radoslaw Debiec, Christopher P Nelson, Klaus Stark, Martin D Tobin, Peter W Macfarlane, Maciej Tomaszewski, Nilesh J Samani, Christian Hengstenberg

  Circulation. Cardiovascular genetics. 01/2011; 4(2):134-8.

  Early repolarization (ER), defined by J-point elevation in 12-lead ECG, was recently associated with increased risk for idiopathic ventricular fibrillation and cardiovascular mortality. TheEarly repolarization (ER), defined by J-point elevation in 12-lead ECG, was recently associated with increased risk for idiopathic ventricular fibrillation and cardiovascular mortality. The determinants of ER are unknown. We investigated its heritability in a large, family-based cohort. The study sample comprised 1877 individuals from 505 white nuclear families representative of the British general population. Standard 12-lead ECGs were evaluated for the presence of ER, defined as J-point elevation of ≥0.1 mV in at least 2 adjacent inferior (II, III, and aVF) or anterolateral (I, aVL, and V(4) through V(6)) leads. Narrow sense heritability estimates were computed adjusting for age, age(2), and sex. The prevalence of ER was 7.7% (n=145) in the whole cohort, 5.9% (n=56) in parents, and 9.6% (n=89) in offspring. Heritability estimate for the presence of ER was calculated at h(2)=0.49 (standard error=0.14; P=2.7*10(-4)) and was higher when restricted to its presence in inferior leads (h(2)=0.61, standard error=0.18, P=4.3*10(-4)) or for the notching ER morphology (h(2)=0.81, standard error=0.19, P=2.4*10(-5)). Individuals with at least 1 affected parent had a 2.5-fold increased risk for presenting with ER on ECG (odds ratio, 2.54; 95% confidence interval, 1.33 to 4.84; P=0.005). Familial transmission was more frequent when the mother was affected (odds ratio, 3.84; 95% confidence interval, 1.41 to 10.43; P=0.008) than when the father was affected (odds ratio, 1.82; 95% confidence interval, 0.82 to 4.03; P=0.141), although this difference was not statistically significant (P=0.18). ER is a heritable phenotype. Offspring of ER-positive parents have a 2.5-fold increased risk of presenting with ER on their ECG.

• Automated electrocardiogram interpretation programs versus cardiologists' triage decision making based on teletransmitted data in patients with suspected acute coronary syndrome.

  Authors: Elaine N Clark, Maria Sejersten, Peter Clemmensen, Peter W Macfarlane

  The American journal of cardiology. 12/2010; 106(12):1696-702.

  The aims of this study were to assess the effectiveness of 2 automated electrocardiogram interpretation programs in patients with suspected acute coronary syndrome transported to hospital byThe aims of this study were to assess the effectiveness of 2 automated electrocardiogram interpretation programs in patients with suspected acute coronary syndrome transported to hospital by ambulance in 1 rural region of Denmark with hospital discharge diagnosis used as the gold standard and to assess the effectiveness of cardiologists' triage decisions for these patients based on initial electrocardiogram. Twelve-lead electrocardiograms were recorded in ambulances using a LIFEPAK 12 monitor/defibrillator (Physio-Control, Inc., Redmond, Washington) and transmitted digitally to an attending cardiologist. If a diagnosis of ST elevation myocardial infarction was made, a patient was taken to a regional interventional center for primary percutaneous coronary intervention or to a local hospital. One thousand consecutive digital electrocardiograms and corresponding interpretations from LIFEPAK 12 were available, and these were subsequently interpreted by the University of Glasgow program. Electrocardiogram interpretations and cardiologists' decisions were compared to hospital discharge diagnoses. The sensitivity, specificity, and positive predictive values for a report of ST elevation myocardial infarction with respect to discharge diagnosis were 78%, 91%, and 81% for LIFEPAK 12 and 78%, 94%, and 87% for the Glasgow program. Corresponding data for attending cardiologists were 85%, 90%, and 81%. In conclusion, the Glasgow program had significantly higher specificity than the LIFEPAK 12 program (p = 0.02) and the cardiologists (p = 0.004). Triage decisions were effective, with good agreement between cardiologists' decisions and discharge diagnoses.

• Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.

  Authors: Naveed Sattar, David Preiss, Heather M Murray, Paul Welsh, Brendan M Buckley, Anton J M de Craen, Sreenivasa Rao Kondapally Seshasai, John J McMurray, Dilys J Freeman, J Wouter Jukema [......] Terje R Pedersen, Thomas J Cook, Antonio M Gotto, Michael B Clearfield, John R Downs, Haruo Nakamura, Yasuo Ohashi, Kyoichi Mizuno, Kausik K Ray, Ian Ford

  Lancet. 02/2010; 375(9716):735-42.

  Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublishedTrials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublished data whether any relation exists between statin use and development of diabetes. We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009, for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ transplants or who needed haemodialysis. We used the I(2) statistic to measure heterogeneity between trials and calculated risk estimates for incident diabetes with random-effect meta-analysis. We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% CI 1.02-1.17), with little heterogeneity (I(2)=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150-852) patients with statins for 4 years resulted in one extra case of diabetes. Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change. None.

• Unraveling the Directional Link between Adiposity and Inflammation: A Bidirectional Mendelian Randomization Approach.

  Authors: Paul Welsh, Eliana Polisecki, Michele Robertson, Sabine Jahn, Brendan M Buckley, Anton J M de Craen, Ian Ford, J Wouter Jukema, Peter W Macfarlane, Chris J Packard, David J Stott, Rudi G J Westendorp, James Shepherd, Aroon D Hingorani, George Davey Smith, Ernst Schaefer, Naveed Sattar

  The Journal of clinical endocrinology and metabolism. 11/2009;

  Context: Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not been proven. Objective: The aim of the studyContext: Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not been proven. Objective: The aim of the study was to explore the causal direction of the relationship between adiposity and inflammation using a bidirectional Mendelian randomization approach. Methods: In the PROSPER study of 5804 elderly patients, we related C-reactive protein (CRP) single nucleotide polymorphisms (SNPs) (rs1800947 and rs1205) and adiposity SNPs (FTO and MC4R) to body mass index (BMI) as well as circulating levels of CRP and leptin. We gave each individual two allele scores ranging from zero to 4, counting each pair of alleles related to CRP levels or BMI. Results: With increasing CRP allele score, there was a stepwise decrease in CRP levels (P for trend < 0.0001) and a 1.98 mg/liter difference between extremes of the allele score distribution, but there was no associated change in BMI or leptin levels (P >/= 0.89). By contrast, adiposity allele score was associated with 1) an increase in BMI (1.2 kg/m(2) difference between extremes; P for trend 0.002); 2) an increase in circulating leptin (5.77 ng/ml difference between extremes; P for trend 0.0027); and 3) increased CRP levels (1.24 mg/liter difference between extremes; P for trend 0.002). Conclusions: Greater adiposity conferred by FTO and MC4R SNPs led to higher CRP levels, with no evidence for any reverse pathway. Future studies should extend our findings to other circulating inflammatory parameters. This study illustrates the potential power of Mendelian randomization to dissect directions of causality between intercorrelated metabolic factors.

• Lipoprotein-associated phospholipase A(2), inflammatory biomarkers, and risk of cardiovascular disease in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).

  Authors: Muriel J Caslake, Chris J Packard, Michele Robertson, Josephine Cooney, Jeanenne J Nelson, Ian Ford, Allan Gaw, J Wouter Jukema, Peter W Macfarlane, David J Stott, James Shepherd

  Atherosclerosis. 11/2009;

  OBJECTIVE: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an inflammatory biomarker that circulates mainly bound to LDL. We evaluated the association of Lp-PLA(2) with vascular events inOBJECTIVE: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an inflammatory biomarker that circulates mainly bound to LDL. We evaluated the association of Lp-PLA(2) with vascular events in the elderly where the importance of LDL is diminished as a risk factor for coronary disease. METHODS: Mass and activity of Lp-PLA(2) were related to risk over 3.2 years for vascular events (definite or suspected death from CHD, non-fatal MI, fatal or non-fatal stroke) in the 2804 men and 3000 women age 70-82 years in the Prospective Study of Pravastatin in the Elderly (PROSPER). RESULTS: Lp-PLA(2) showed a moderate, positive association with risk of a vascular event with hazard ratios of 1.25 (confidence interval (CI) 1.02-1.54) for mass and 1.39 (CI 1.14-1.70) for activity for top versus bottom quartile. Risk associations were attenuated when classical risk factors, lipids and inflammatory markers - C-reactive protein and white cell count - were included in the models. Lp-PLA(2) was unrelated to stroke risk. Inclusion of all three inflammatory markers in multivariate models negated the association of HDL cholesterol with risk (hazard ratio 0.98; CI 0.88-1.10) and increased prediction of coronary events; the C statistic rose from 63.2% to 64.4% (P<0.001). CONCLUSION: In elderly people Lp-PLA(2), alongside other inflammatory indices, is a potential biomarker for vascular events, particularly CHD.

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

  Authors: Naveed Sattar, Heather M Murray, Paul Welsh, Gerard J Blauw, Brendan M Buckley, Stuart Cobbe, Anton J M de Craen, Gordon D Lowe, J Wouter Jukema, Peter W Macfarlane, Michael B Murphy, David J Stott, Rudi G J Westendorp, James Shepherd, Ian Ford, Chris J Packard

  PLoS medicine. 06/2009; 6(6):e1000099.

  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 testedBACKGROUND: 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.

• Leptin predicts diabetes but not CVD: results from a large prospective study in the elderly.

  Authors: Paul Welsh, Heather M Murray, Brendan M Buckley, Anton J M de Craen, Ian Ford, J Wouter Jukema, Peter W Macfarlane, Chris J Packard, David J Stott, Rudi G J Westendorp, James Shepherd, Naveed Sattar

  Diabetes care. 12/2008;

  Objective: To clarify the association of circulating levels of leptin with risk for CVD events and new onset diabetes in men and women. Research Design and Methods: We related baseline leptin levelsObjective: To clarify the association of circulating levels of leptin with risk for CVD events and new onset diabetes in men and women. Research Design and Methods: We related baseline leptin levels to CVD events (n=864) and incident diabetes (n=289) in the elderly (n=5672) over 3.2 years follow-up. Results: In treatment, age, and country adjusted models, leptin was not associated with risk of CVD in men (HR 1.02 [95%CI 0.90-1.16] per unit log-leptin increase) or women (HR 1.05 [0.91-1.20]), but did associate with risk for diabetes in men (HR 2.75 [2.14-3.52]) and women (HR 1.54 [1.22-1.94]). After adjusting for classical risk factors, BMI, CRP and glucose, the diabetes association in men retained significance (HR 1.85 [1.30-2.63]), but not in women (HR 0.89 [0.64-1.26]). Conclusions: Leptin, like other markers of adiposity in general, is more strongly related to risk of diabetes than CVD in the elderly.

• Can metabolic syndrome usefully predict cardiovascular disease and diabetes? Outcome data from two prospective studies.

  Authors: Naveed Sattar, Alex McConnachie, A Gerald Shaper, Gerard J Blauw, Brendan M Buckley, Anton J de Craen, Ian Ford, Nita G Forouhi, Dilys J Freeman, J Wouter Jukema, Lucy Lennon, Peter W Macfarlane, Michael B Murphy, Chris J Packard, David J Stott, Rudi G Westendorp, Peter H Whincup, James Shepherd, S Goya Wannamethee

  Lancet. 07/2008; 371(9628):1927-35.

  BACKGROUND: Clinical use of criteria for metabolic syndrome to simultaneously predict risk of cardiovascular disease and diabetes remains uncertain. We investigated to what extent metabolic syndromeBACKGROUND: Clinical use of criteria for metabolic syndrome to simultaneously predict risk of cardiovascular disease and diabetes remains uncertain. We investigated to what extent metabolic syndrome and its individual components were related to risk for these two diseases in elderly populations. METHODS: We related metabolic syndrome (defined on the basis of criteria from the Third Report of the National Cholesterol Education Program) and its five individual components to the risk of events of incident cardiovascular disease and type 2 diabetes in 4812 non-diabetic individuals aged 70-82 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). We corroborated these data in a second prospective study (the British Regional Heart Study [BRHS]) of 2737 non-diabetic men aged 60-79 years. FINDINGS: In PROSPER, 772 cases of incident cardiovascular disease and 287 of diabetes occurred over 3.2 years. Metabolic syndrome was not associated with increased risk of cardiovascular disease in those without baseline disease (hazard ratio 1.07 [95% CI 0.86-1.32]) but was associated with increased risk of diabetes (4.41 [3.33-5.84]) as was each of its components, particularly fasting glucose (18.4 [13.9-24.5]). Results were similar in participants with existing cardiovascular disease. In BRHS, 440 cases of incident cardiovascular disease and 105 of diabetes occurred over 7 years. Metabolic syndrome was modestly associated with incident cardiovascular disease (relative risk 1.27 [1.04-1.56]) despite strong association with diabetes (7.47 [4.90-11.46]). In both studies, body-mass index or waist circumference, triglyceride, and glucose cutoff points were not associated with risk of cardiovascular disease, but all five components were associated with risk of new-onset diabetes. INTERPRETATION: Metabolic syndrome and its components are associated with type 2 diabetes but have weak or no association with vascular risk in elderly populations, suggesting that attempts to define criteria that simultaneously predict risk for both cardiovascular disease and diabetes are unhelpful. Clinical focus should remain on establishing optimum risk algorithms for each disease.

• Gender and effects of a common genetic variant in the NOS1 regulator NOS1AP on cardiac repolarization in 3761 individuals from two independent populations.

  Authors: Martin D Tobin, Mika Kähönen, Peter Braund, Tuomo Nieminen, Cother Hajat, Maciej Tomaszewski, Jari Viik, Rami Lehtinen, G. Andre Ng, Peter W Macfarlane, Paul R Burton, Terho Lehtimäki, Nilesh J Samani

  International journal of epidemiology. 06/2008;

  BACKGROUND: A longer heart-rate corrected QT interval (QTc) is associated with increased risk of ventricular arrhythmias. Women have longer resting QTc and are more likely than men to developBACKGROUND: A longer heart-rate corrected QT interval (QTc) is associated with increased risk of ventricular arrhythmias. Women have longer resting QTc and are more likely than men to develop drug-induced QT prolongation. Recent studies have shown association between resting QTc and a common variant (rs10494366) of the NOS1 regulator, NOS1AP. We investigated the association between rs10494366 in NOS1AP and QTc, and assessed gender-specific NOS1AP associations with QTc during rest and after exercise. METHODS: We investigated the SNP associations with resting QTc in 919 women and 918 men from 504 representative families in the UK GRAPHIC study, and with QTc at rest and at 3 min recovery after exercise in 699 women and 1225 men referred for exercise testing in the Finnish FINCAVAS study. RESULTS: In the GRAPHIC study the minor allele (G) of the NOS1AP SNP rs10494366 prolonged QTc by 4.59 ms (95% CI 2.77-6.40; P = 7.63/10(7)) in women, but only by 1.62 ms (95% CI -0.15 to 3.38; P = 0.073) in men (gender-SNP interaction term P = 0.025). In the FINCAVAS study the G allele significantly prolonged QTc in both women (P = 0.0063) and men (P = 0.0043) at 3 min recovery after exercise, but at rest an association was only seen in women (P = 0.020 excluding outliers). CONCLUSIONS: A common NOS1AP variant prolongs QTc with a difference between genders. Further studies should aim to confirm this finding and to assess whether NOS1AP genotype influences the risk of drug-induced QT prolongation and risk of consequent arrhythmias.

• Length of the QT interval: determinants and prognostic implications in a population-based prospective study of older men.

  Authors: Syed Mohammad Afzal Sohaib, Olia Papacosta, Richard W Morris, Peter W Macfarlane, Peter H Whincup

  Journal of electrocardiology. 04/2008;

  OBJECTIVE: We examined potential determinants and prognostic value of the corrected QT interval (QTc). DESIGN: A total of 4252 British men aged 60 to 79 years had a resting 12-lead electrocardiogram.OBJECTIVE: We examined potential determinants and prognostic value of the corrected QT interval (QTc). DESIGN: A total of 4252 British men aged 60 to 79 years had a resting 12-lead electrocardiogram. Potential determinants of the QTc were assessed using multivariable regression. Men were followed up for 7 years. RESULTS: A 1 standard deviation increase in QTc (26 milliseconds) was associated with increased all-cause mortality (hazard ratio, 1.13; 95% confidence interval, 1.05-1.22). Longer QTc was associated with increasing age, preexisting coronary heart disease, and a range of drugs. Shorter QTc was present in diabetics and smokers. Corrected QT interval was related inversely with serum potassium and calcium and positively with serum urate, sodium, and systolic blood pressure. The relation of QTc to all-cause mortality was independent of adjustment for these factors. CONCLUSIONS: Age, preexisting coronary heart disease, certain medications and biochemical factors, and diabetes are independently associated with QTc. Corrected QT interval is an independent predictor of all-cause mortality.

• Association between apolipoprotein E4 and cognitive decline in elderly adults.

  Authors: Chris J Packard, Rudi G J Westendorp, David J Stott, Muriel J Caslake, Heather M Murray, James Shepherd, Gerard J Blauw, Michael B Murphy, Edward L E M Bollen, Brendan M Buckley [......] Ian Ford, Allan Gaw, Michael Hyland, J Wouter Jukema, Adriaan M Kamper, Peter W Macfarlane, Jellemer Jolles, Ivan J Perry, Brian J Sweeney, Cillian Twomey

  Journal of the American Geriatrics Society. 11/2007; 55(11):1777-85.

  OBJECTIVE: To determine the influence of apolipoprotein E on cognitive decline in a cohort of elderly men and women. DESIGN: Prospective study. SETTING: Scotland, Ireland, and the Netherlands.OBJECTIVE: To determine the influence of apolipoprotein E on cognitive decline in a cohort of elderly men and women. DESIGN: Prospective study. SETTING: Scotland, Ireland, and the Netherlands. PARTICIPANTS: Five thousand eight hundred four subjects aged 70 to 82 from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). MEASUREMENTS: Subjects were assessed at baseline and over a mean 3.2-year (range 0.7-4.2) follow-up for memory (Picture-Word Recall), speed of information processing (Stroop and Letter-Digit Coding), global cognitive function (Mini-Mental State Examination), and activities of daily living. RESULTS: At baseline, subjects with apolipoprotein E(4) versus those without E(4) had poorer memory performance (mean score difference -0.20 (95% confidence interval (CI)=-0.31 to -0.09) for immediate recall and -0.32 (95% CI=-0.48 to -0.16) for delayed recall and slower information processing (difference in Stroop, 2.79 seconds, (95% CI=1.20-4.28); Letter-Digit score, -0.36, (95% CI=-0.77-0.05). Subjects with apolipoprotein E(4) showed a greater decline in immediate (-0.22, 95% CI=-0.33 to -0.11) and delayed (-0.30, 95% CI=-0.46 to -0.15) memory scores but no significant change in speed of information processing (Stroop, P=.17; Letter-Digit, P=.06). Memory scores decreased 2.5% from baseline in those without E(4), 4.3% in E(4) heterozygotes (P=.01 for immediate and P=.03 for delayed, vs no E(4)) and 8.9% to 13.8% in E(4) homozygotes (P=.04 for immediate and P=.004 for delayed, vs heterozygotes). Apolipoprotein E(4) was associated with greater decline in instrumental activities of daily living (P<.001). Cognitive decline was not associated with lipoprotein levels. CONCLUSION: Findings in PROSPER indicate that E(4) is associated with more-rapid cognitive decline and may, therefore, predispose to dementia.

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

  Authors: Ian Ford, Heather Murray, Chris J Packard, James Shepherd, Peter W Macfarlane, Stuart M Cobbe

  The New England journal of medicine. 10/2007; 357(15):1477-86.

  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 myocardialBACKGROUND: 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.

• Localization of accessory pathways in the Wolff-Parkinson-White pattern--physician versus computer interpretation of the same algorithm.

  Authors: Andrew D McGavigan, Elaine Clark, F Russell Quinn, Andrew C Rankin, Peter W Macfarlane

  Pacing and clinical electrophysiology : PACE. 09/2007; 30(8):998-1002.

  BACKGROUND: There are several published algorithms for the prediction of accessory pathway (AP) location in the Wolff-Parkinson-White syndrome from the 12-lead electrocardiogram (ECG). Most depend onBACKGROUND: There are several published algorithms for the prediction of accessory pathway (AP) location in the Wolff-Parkinson-White syndrome from the 12-lead electrocardiogram (ECG). Most depend on stepwise criteria, and minor disagreements between observers over QRS transition point or delta wave axis may lead to different classification of pathway location. We compared the utility of a computerized program in identifying pathway location from the ECG using the algorithm published by Fitzpatrick and coworkers(3) against physician assessment with the same algorithm. METHODS: Thirty-one 12-lead ECGs with an overt preexcitation pattern were examined by three physicians and AP localized to one of eight anatomical sites using the Fitzpatrick algorithm, with disagreements resolved by consensus. Similarly, pathway location was determined by the Glasgow ECG program with the Fitzpatrick algorithm incorporated into its logic. RESULTS: The agreement between each physician and their consensus was 28/31, 29/31, and 29/31. Similarly, assessment by the Glasgow program produced agreement with the physician consensus in 29/31 cases. Of the 24 patients who underwent radiofrequency ablation, the program localized the pathway to the true or adjacent annular region in 20, compared to 20/24 by physician assessment of the algorithm, producing a similar predictive accuracy to published data. CONCLUSION: This study has shown that incorporation of the Fitzpatrick algorithm for AP location into a widely used computer program results in the same level of performance as that of experienced physicians and may be useful in clinical practice as an aid to referral for electrophysiological study and ablation.

• Evaluation of the electrocardiographic criteria for left ventricular hypertrophy.

  Authors: Iain Morrison, Elaine Clark, Peter W Macfarlane

  Anadolu kardiyoloji dergisi : AKD = the Anatolian journal of cardiology. 08/2007; 7 Suppl 1:159-63.

  OBJECTIVE: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular (CV) mortality.This study compared different criteria including Sokolow-Lyon and Cornell, in terms ofOBJECTIVE: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular (CV) mortality.This study compared different criteria including Sokolow-Lyon and Cornell, in terms of voltage and voltage-QRS-duration products, as well as point-scoring systems such as the Romhilt-Estes, Perugia and Glasgow-Royal-Infirmary modified Romhilt-Estes score. METHODS: Patients undergoing echocardiography were recruited from the cardiology department in Glasgow Royal Infirmary. Echocardiographically derived left ventricular mass was indexed to body surface area and using sex dependent thresholds, LVH was determined. Electrocardiograms (ECG) were processed using The University of Glasgow Analysis Program, permitting different LVH criteria to be calculated and evaluated. Inclusion criteria for this study were that the patients had a technically adequate echocardiogram and ECG. RESULTS: The main analysis used 51 male and 76 female patients. At published thresholds, the Lewis index gave the greatest sensitivity of the voltage criteria (12%). However, adjusted to 95% specificity, the Cornell index produced the greatest sensitivity at 19%. The best voltage-duration product was the Cornell product that gave 15% sensitivity and 19% when adjusted to 95% specificity.The point scoring systems proved to be the most accurate with the Perugia score being 22% sensitive and the Glasgow Royal Infirmary modified Romhilt-Estes score 24 % sensitive, both at 95% specificity. CONCLUSION: This study finds that ECG criteria for LVH that use only voltage are relatively poor predictors of LVH. This study also finds that the best criteria for assessing LVH are the point scoring criteria, in particular the Glasgow Royal Infirmary Modified Romhilt-Estes score.