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1.  A Systematic Review Concerning the Relation between the Sympathetic Nervous System and Heart Failure with Preserved Left Ventricular Ejection Fraction 
PLoS ONE  2015;10(2):e0117332.
Heart failure with preserved left ventricular ejection fraction (HFPEF) affects about half of all patients diagnosed with heart failure. The pathophysiological aspect of this complex disease state has been extensively explored, yet it is still not fully understood. Since the sympathetic nervous system is related to the development of systolic HF, we hypothesized that an increased sympathetic nerve activation (SNA) is also related to the development of HFPEF. This review summarizes the available literature regarding the relation between HFPEF and SNA.
Methods and Results
Electronic databases and reference lists through April 2014 were searched resulting in 7722 unique articles. Three authors independently evaluated citation titles and abstracts, resulting in 77 articles reporting about the role of the sympathetic nervous system and HFPEF. Of these 77 articles, 15 were included for critical appraisal: 6 animal and 9 human studies. Based on the critical appraisal, we selected 9 articles (3 animal, 6 human) for further analysis. In all the animal studies, isoproterenol was administered to mimic an increased sympathetic activity. In human studies, different modalities for assessment of sympathetic activity were used. The studies selected for further evaluation reported a clear relation between HFPEF and SNA.
Current literature confirms a relation between increased SNA and HFPEF. However, current literature is not able to distinguish whether enhanced SNA results in HFPEF, or HFPEF results in enhanced SNA. The most likely setting is a vicious circle in which HFPEF and SNA sustain each other.
PMCID: PMC4319815  PMID: 25658630
2.  Mutation Positive Arrhyhmogenic Right Ventricular Dysplasia/Cardiomyopathy: The Triangle of Dysplasia Displaced 
The traditional description of the Triangle of Dysplasia in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) predates genetic testing and excludes biventricular phenotypes.
Methods and Results
We analyzed Cardiac Magnetic Resonance (CMR) studies of 74 mutation-positive ARVD/C patients for regional abnormalities on a 5-segment RV and 17-segment LV model. The location of electroanatomic endo- and epicardial scar and site of successful VT ablation was recorded in 11 ARVD/C subjects. Among 54/74 (73%) subjects with abnormal CMR, the RV was abnormal in almost all (96%), and 52% had biventricular involvement. Isolated LV abnormalities were uncommon (4%). Dyskinetic basal inferior wall (94%) was the most prevalent RV abnormality, followed by basal anterior wall (87%) dyskinesis. Subepicardial fat infiltration in the posterolateral LV (80%) was the most frequent LV abnormality. Similar to CMR data, voltage maps revealed scar (<0.5 mV) in the RV basal inferior wall (100%), followed by the RV basal anterior wall (64%) and LV posterolateral wall (45%). All 16 RV VTs originated from the basal inferior wall (50%) or basal anterior wall (50%). Of 3 LV VTs, 2 localized to the posterolateral wall. In both modalities, RV apical involvement never occurred in isolation.
Mutation-positive ARVD/C exhibits a previously unrecognized characteristic pattern of disease involving the basal inferior and anterior RV, and the posterolateral LV. The RV apex is only involved in advanced ARVD/C, typically as a part of global RV involvement. These results displace the RV apex from the Triangle of Dysplasia, and provide insights into the pathophysiology of ARVD/C.
PMCID: PMC3971054  PMID: 23889974
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy; magnetic resonance imaging; electroanatomic mapping; ventricular tachcardia; phenotype; genetics; implantable cardioverter defibrillator
3.  Secretory Phospholipase A2-IIA and Cardiovascular Disease 
Holmes, Michael V. | Simon, Tabassome | Exeter, Holly J. | Folkersen, Lasse | Asselbergs, Folkert W. | Guardiola, Montse | Cooper, Jackie A. | Palmen, Jutta | Hubacek, Jaroslav A. | Carruthers, Kathryn F. | Horne, Benjamin D. | Brunisholz, Kimberly D. | Mega, Jessica L. | van Iperen, Erik P.A. | Li, Mingyao | Leusink, Maarten | Trompet, Stella | Verschuren, Jeffrey J.W. | Hovingh, G. Kees | Dehghan, Abbas | Nelson, Christopher P. | Kotti, Salma | Danchin, Nicolas | Scholz, Markus | Haase, Christiane L. | Rothenbacher, Dietrich | Swerdlow, Daniel I. | Kuchenbaecker, Karoline B. | Staines-Urias, Eleonora | Goel, Anuj | van 't Hooft, Ferdinand | Gertow, Karl | de Faire, Ulf | Panayiotou, Andrie G. | Tremoli, Elena | Baldassarre, Damiano | Veglia, Fabrizio | Holdt, Lesca M. | Beutner, Frank | Gansevoort, Ron T. | Navis, Gerjan J. | Mateo Leach, Irene | Breitling, Lutz P. | Brenner, Hermann | Thiery, Joachim | Dallmeier, Dhayana | Franco-Cereceda, Anders | Boer, Jolanda M.A. | Stephens, Jeffrey W. | Hofker, Marten H. | Tedgui, Alain | Hofman, Albert | Uitterlinden, André G. | Adamkova, Vera | Pitha, Jan | Onland-Moret, N. Charlotte | Cramer, Maarten J. | Nathoe, Hendrik M. | Spiering, Wilko | Klungel, Olaf H. | Kumari, Meena | Whincup, Peter H. | Morrow, David A. | Braund, Peter S. | Hall, Alistair S. | Olsson, Anders G. | Doevendans, Pieter A. | Trip, Mieke D. | Tobin, Martin D. | Hamsten, Anders | Watkins, Hugh | Koenig, Wolfgang | Nicolaides, Andrew N. | Teupser, Daniel | Day, Ian N.M. | Carlquist, John F. | Gaunt, Tom R. | Ford, Ian | Sattar, Naveed | Tsimikas, Sotirios | Schwartz, Gregory G. | Lawlor, Debbie A. | Morris, Richard W. | Sandhu, Manjinder S. | Poledne, Rudolf | Maitland-van der Zee, Anke H. | Khaw, Kay-Tee | Keating, Brendan J. | van der Harst, Pim | Price, Jackie F. | Mehta, Shamir R. | Yusuf, Salim | Witteman, Jaqueline C.M. | Franco, Oscar H. | Jukema, J. Wouter | de Knijff, Peter | Tybjaerg-Hansen, Anne | Rader, Daniel J. | Farrall, Martin | Samani, Nilesh J. | Kivimaki, Mika | Fox, Keith A.A. | Humphries, Steve E. | Anderson, Jeffrey L. | Boekholdt, S. Matthijs | Palmer, Tom M. | Eriksson, Per | Paré, Guillaume | Hingorani, Aroon D. | Sabatine, Marc S. | Mallat, Ziad | Casas, Juan P. | Talmud, Philippa J.
This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.
Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.
We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.
PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.
Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
PMCID: PMC3826105  PMID: 23916927
cardiovascular diseases; drug development; epidemiology; genetics; Mendelian randomization; ACS, acute coronary syndrome(s); CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; MVE, major vascular events; OR, odds ratio; RCT, randomized clinical trial; SNP, single-nucleotide polymorphism; sPLA2, secretory phospholipase A2
4.  Atherosclerotic renal artery stenosis is prevalent in cardiorenal patients but not associated with left ventricular function and myocardial fibrosis as assessed by cardiac magnetic resonance imaging 
Atherosclerotic renal artery stenosis (ARAS) is common in cardiovascular diseases and associated with hypertension, renal dysfunction and/or heart failure. There is a paucity of data about the prevalence and the role of ARAS in the pathophysiology of combined chronic heart failure (CHF) and chronic kidney disease (CKD). We investigated the prevalence in patients with combined CHF/CKD and its association with renal function, cardiac dysfunction and the presence and extent of myocardial fibrosis.
The EPOCARES study (ClinTrialsNCT00356733) investigates the role of erythropoietin in anaemic patients with combined CHF/CKD. Eligible subjects underwent combined cardiac magnetic resonance imaging (cMRI), including late gadolinium enhancement, with magnetic resonance angiography of the renal arteries (MRA).
MR study was performed in 37 patients (median age 74 years, eGFR 37.4 ± 15.6 ml/min, left ventricular ejection fraction (LVEF) 43.3 ± 11.2%), of which 21 (56.8%) had ARAS (defined as stenosis >50%). Of these 21 subjects, 8 (21.6%) had more severe ARAS >70% and 8 (21.6%) had a bilateral ARAS >50% (or previous bilateral PTA). There were no differences in age, NT-proBNP levels and medication profile between patients with ARAS versus those without. Renal function declined with the severity of ARAS (p = 0.03), although this was not significantly different between patients with ARAS versus those without. Diabetes mellitus was more prevalent in patients without ARAS (56.3%) against those with ARAS (23.8%) (p = 0.04). The presence and extent of late gadolinium enhancement, depicting myocardial fibrosis, did not differ (p = 0.80), nor did end diastolic volume (p = 0.60), left ventricular mass index (p = 0.11) or LVEF (p = 0.15). Neither was there a difference in the presence of an ischemic pattern of late enhancement in patients with ARAS versus those without.
ARAS is prevalent in combined CHF/CKD and its severity is associated with a decline in renal function. However, its presence does not correlate with a worse LVEF, a higher left ventricular mass or with the presence and extent of myocardial fibrosis. Further research is required for the role of ARAS in the pathophysiology of combined chronic heart and renal failure.
PMCID: PMC3470969  PMID: 22989293
Cardiorenal failure; Atherosclerotic renal artery stenosis; Magnetic resonance imaging; Late gadolinium enhancement
5.  Echocardiographic prediction of outcome after cardiac resynchronization therapy: conventional methods and recent developments 
Heart Failure Reviews  2010;16(3):235-250.
Echocardiography plays an important role in patient assessment before cardiac resynchronization therapy (CRT) and can monitor many of its mechanical effects in heart failure patients. Encouraged by the highly variable individual response observed in the major CRT trials, echocardiography-based measurements of mechanical dyssynchrony have been extensively investigated with the aim of improving response prediction and CRT delivery. Despite recent setbacks, these techniques have continued to develop in order to overcome some of their initial flaws and limitations. This review discusses the concepts and rationale of the available echocardiographic techniques, highlighting newer quantification methods and discussing some of the unsolved issues that need to be addressed.
PMCID: PMC3074077  PMID: 21104122
Heart failure; Cardiac resynchronization therapy; Echocardiography; Mechanical dyssynchrony
6.  Screening for proximal coronary artery anomalies with 3-dimensional MR coronary angiography 
Under 35 years of age, 14% of sudden cardiac death in athletes is caused by a coronary artery anomaly (CAA). Free-breathing 3-dimensional magnetic resonance coronary angiography (3D-MRCA) has the potential to screen for CAA in athletes and non-athletes as an addition to a clinical cardiac MRI protocol. A 360 healthy men and women (207 athletes and 153 non-athletes) aged 18–60 years (mean age 31 ± 11 years, 37% women) underwent standard cardiac MRI with an additional 3D-MRCA within a maximum of 10 min scan time. The 3D-MRCA was screened for CAA. A 335 (93%) subjects had a technically satisfactory 3D-MRCA of which 4 (1%) showed a malignant variant of the right coronary artery (RCA) origin running between the aorta and the pulmonary trunk. Additional findings included three subjects with ventral rotation of the RCA with kinking and possible proximal stenosis, one person with additional stenosis and six persons with proximal myocardial bridging of the left anterior descending coronary artery. Coronary CT-angiography (CTA) was offered to persons with CAA (the CAA was confirmed in three, while one person declined CTA) and stenosis (the ventral rotation of the RCA was confirmed in two but without stenosis, while two people declined CTA). Overall 3D MRCA quality was better in athletes due to lower heart rates resulting in longer end-diastolic resting periods. This also enabled faster scan sequences. A 3D-MRCA can be used as part of the standard cardiac MRI protocol to screen young competitive athletes and non-athletes for anomalous proximal coronary arteries.
PMCID: PMC2898111  PMID: 20339919
Athletes; Magnetic resonance coronary angiography; Coronary artery anomalies; Coronary artery disease; Myocardial bridging
7.  Echocardiographic Screening Results in Patients with Tuberous Sclerosis Complex 
Texas Heart Institute Journal  2010;37(3):280-283.
We sought to examine the frequency of abnormal echocardiographic findings in patients with tuberous sclerosis complex.
In a retrospective cohort study, we included all patients with known tuberous sclerosis complex who had been sent to our cardiology department for echocardiographic screening from 1995 through August 2003 (n=56). Two research scientists independently reviewed the reports of the echocardiographic screening examinations for abnormal findings. We used descriptive statistics, the Mann-Whitney U test, and the χ2 test.
The mean age of patients included in the study was 35 years (range, 12–73 yr); 23 patients were male. Abnormal findings were seen in 22 patients (39%). The most common abnormal findings were focal areas of increased intramyocardial echogenicity, which were seen in 16 patients (29%). The clinical consequence of this finding is still unknown.
We conclude that echocardiographic abnormalities are common in patients with tuberous sclerosis complex.
PMCID: PMC2879195  PMID: 20548802
Adolescent; adult; child; echocardiography; hamartoma/complications; heart neoplasms/ultrasonography; rhabdomyoma/ultrasonography; tuberous sclerosis/complications
8.  Early recognition of heart failure in patients with diabetes type 2 in primary care. A prospective diagnostic efficiency study. (UHFO-DM2) 
BMC Public Health  2009;9:479.
We hypothesize that the prevalence of unknown heart failure in diabetic patients aged 60 years and over is relatively high (15% or more) and that a cost-effective strategy can be developed to detect heart failure in these patients. The strategy is expected to include some signs and symptoms (such as dyspnoea, orthopnoea, pulmonary crepitations and laterally displaced apical beat), natriuretic peptide measurements (Amino-terminal B-type natriuretic peptide) and possibly electrocardiography. In a subset of patients straightforward echocardiography may show to be cost-effective. With information from our study the detection of previously unknown heart failure in diabetic patients could be improved and enable the physician to initiate beneficial morbidity and mortality reducing heart failure treatment more timely.
Primary objectives
- To assess the prevalence of (previously unrecognised) heart failure in primary care patients with diabetes type 2.
- To establish the most cost-effective diagnostic strategy to detect unrecognised heart failure in these patients.
Secondary objectives
- To assess the impact of heart failure, and the combination of a new diagnosis with accordingly treatment in patients with diabetes type 2 on health status.
Design: A prospective diagnostic efficiency study.
Patient population: Patients aged 60 years and older with diabetes type 2 from primary care, enlisted with the diabetes service of the Diagnostic Center in Etten-Leur (SHL)
All participants will be investigated at the cardiology out-patient department of the regional hospital (Oosterschelde Hospital in Goes, Zeeland, the Netherlands) during a single 1.5 hour standardised diagnostic assessment, including history taking, physical examination, electrocardiography, echocardiography, blood tests, and Health status questionnaires. Patients will be asked if we can contact them afterwards for follow-up and for repeating the questionnaires after three and 12 months.
Main study parameters/endpoints: Prevalence (with exact 95% confidence intervals) of (previously unrecognised) heart failure (systolic and 'isolated' diastolic) and the diagnostic value of signs and symptoms, NT-proBNP, electrocardiography and a combination of these items. The cost-effectiveness of different diagnostic strategies. Impact of heart failure and the combination of a new diagnosis with accordingly treatment on health status.
Trial registration
CCMO register NL2271704108
PMCID: PMC2804618  PMID: 20025758
9.  Is there a role for CT coronary angiography in patients with symptomatic angina? Effect of coronary calcium score on identification of stenosis 
Present guidelines discourage the use of CT coronary angiography (CTCA) in symptomatic angina patients. We examined the relation between coronary calcium score (CS) and the performance of CTCA in patients with stable and unstable angina in order to understand under which conditions CTCA might be a gate-keeper to conventional coronary angiography (CCA) in such patients. We included 360 patients between 50 and 70 years old with stable and unstable angina who were clinically referred for CCA irrespective of CS. Patients received CS and CCTA on 64-slice scanners in a multicenter cross-sectional trial. The institutional review board approved the study. Diagnostic performance of CTCA to detect or rule out significant coronary artery disease was calculated on a per patient level in pre-defined CS categories. The prevalence of significant coronary artery disease strongly increased with CS. Negative CTCA were associated with a negative likelihood ratio of <0.1 independent of CS. Positive CTCA was associated with a high positive likelihood ratio of 9.4 if CS was <10. However, for higher CS the positive likelihood ratio never exceeded 3.0 and for CS >400 it decreased to 1.3. In the 62 (17%) patients with CS <10, CTCA reliably identified the 42 (68%) of these patients without significant CAD, at no false negative CTCA scans. In symptomatic angina patients, a negative CTCA reliably excludes significant CAD but the additional value of CTCA decreases sharply with CS >10 and especially with CS >400. In patients with CS <10, CTCA provides excellent diagnostic performance.
PMCID: PMC2784513  PMID: 19649721
Computed tomography; Coronary angiography; Diagnostic performance; Calcium score
10.  Non-invasive cardiac assessment in high risk patients (The GROUND study): rationale, objectives and design of a multi-center randomized controlled clinical trial 
Trials  2008;9:49.
Peripheral arterial disease (PAD) is a common disease associated with a considerably increased risk of future cardiovascular events and most of these patients will die from coronary artery disease (CAD). Screening for silent CAD has become an option with recent non-invasive developments in CT (computed tomography)-angiography and MR (magnetic resonance) stress testing. Screening in combination with more aggressive treatment may improve prognosis. Therefore we propose to study whether a cardiac imaging algorithm, using non-invasive imaging techniques followed by treatment will reduce the risk of cardiovascular disease in PAD patients free from cardiac symptoms.
The GROUND study is designed as a prospective, multi-center, randomized clinical trial. Patients with peripheral arterial disease, but without symptomatic cardiac disease will be asked to participate. All patients receive a proper risk factor management before randomization. Half of the recruited patients will enter the 'control group' and only undergo CT calcium scoring. The other half of the recruited patients (index group) will undergo the non invasive cardiac imaging algorithm followed by evidence-based treatment. First, patients are submitted to CT calcium scoring and CT angiography. Patients with a left main (or equivalent) coronary artery stenosis of > 50% on CT will be referred to a cardiologist without further imaging. All other patients in this group will undergo dobutamine stress magnetic resonance (DSMR) testing. Patients with a DSMR positive for ischemia will also be referred to a cardiologist. These patients are candidates for conventional coronary angiography and cardiac interventions (coronary artery bypass grafting (CABG) or percutaneous cardiac interventions (PCI)), if indicated. All participants of the trial will enter a 5 year follow up period for the occurrence of cardiovascular events. Sequential interim analysis will take place. Based on sample size calculations about 1200 patients are needed to detect a 24% reduction in primary outcome.
The GROUND study will provide insight into the question whether non-invasive cardiac imaging reduces the risk of cardiovascular events in patients with peripheral arterial disease, but without symptoms of coronary artery disease.
Trial registration NCT00189111
PMCID: PMC2519056  PMID: 18673542
11.  Three-dimensional mapping of mechanical activation patterns, contractile dyssynchrony and dyscoordination by two-dimensional strain echocardiography: Rationale and design of a novel software toolbox 
Dyssynchrony of myocardial deformation is usually described in terms of variability only (e.g. standard deviations SD's). A description in terms of the spatio-temporal distribution pattern (vector-analysis) of dyssynchrony or by indices estimating its impact by expressing dyscoordination of shortening in relation to the global ventricular shortening may be preferential. Strain echocardiography by speckle tracking is a new non-invasive, albeit 2-D imaging modality to study myocardial deformation.
A post-processing toolbox was designed to incorporate local, speckle tracking-derived deformation data into a 36 segment 3-D model of the left ventricle. Global left ventricular shortening, standard deviations and vectors of timing of shortening were calculated. The impact of dyssynchrony was estimated by comparing the end-systolic values with either early peak values only (early shortening reserve ESR) or with all peak values (virtual shortening reserve VSR), and by the internal strain fraction (ISF) expressing dyscoordination as the fraction of deformation lost internally due to simultaneous shortening and stretching. These dyssynchrony parameters were compared in 8 volunteers (NL), 8 patients with Wolff-Parkinson-White syndrome (WPW), and 7 patients before (LBBB) and after cardiac resynchronization therapy (CRT).
Dyssynchrony indices merely based on variability failed to detect differences between WPW and NL and failed to demonstrate the effect of CRT. Only the 3-D vector of onset of shortening could distinguish WPW from NL, while at peak shortening and by VSR, ESR and ISF no differences were found. All tested dyssynchrony parameters yielded higher values in LBBB compared to both NL and WPW. CRT reduced the spatial divergence of shortening (both vector magnitude and direction), and improved global ventricular shortening along with reductions in ESR and dyscoordination of shortening expressed by ISF.
Incorporation of local 2-D echocardiographic deformation data into a 3-D model by dedicated software allows a comprehensive analysis of spatio-temporal distribution patterns of myocardial dyssynchrony, of the global left ventricular deformation and of newer indices that may better reflect myocardial dyscoordination and/or impaired ventricular contractile efficiency. The potential value of such an analysis is highlighted in two dyssynchronous pathologies that impose particular challenges to deformation imaging.
PMCID: PMC2429897  PMID: 18513412
12.  Prediction model to estimate presence of coronary artery disease: retrospective pooled analysis of existing cohorts 
Objectives To develop prediction models that better estimate the pretest probability of coronary artery disease in low prevalence populations.
Design Retrospective pooled analysis of individual patient data.
Setting 18 hospitals in Europe and the United States.
Participants Patients with stable chest pain without evidence for previous coronary artery disease, if they were referred for computed tomography (CT) based coronary angiography or catheter based coronary angiography (indicated as low and high prevalence settings, respectively).
Main outcome measures Obstructive coronary artery disease (≥50% diameter stenosis in at least one vessel found on catheter based coronary angiography). Multiple imputation accounted for missing predictors and outcomes, exploiting strong correlation between the two angiography procedures. Predictive models included a basic model (age, sex, symptoms, and setting), clinical model (basic model factors and diabetes, hypertension, dyslipidaemia, and smoking), and extended model (clinical model factors and use of the CT based coronary calcium score). We assessed discrimination (c statistic), calibration, and continuous net reclassification improvement by cross validation for the four largest low prevalence datasets separately and the smaller remaining low prevalence datasets combined.
Results We included 5677 patients (3283 men, 2394 women), of whom 1634 had obstructive coronary artery disease found on catheter based coronary angiography. All potential predictors were significantly associated with the presence of disease in univariable and multivariable analyses. The clinical model improved the prediction, compared with the basic model (cross validated c statistic improvement from 0.77 to 0.79, net reclassification improvement 35%); the coronary calcium score in the extended model was a major predictor (0.79 to 0.88, 102%). Calibration for low prevalence datasets was satisfactory.
Conclusions Updated prediction models including age, sex, symptoms, and cardiovascular risk factors allow for accurate estimation of the pretest probability of coronary artery disease in low prevalence populations. Addition of coronary calcium scores to the prediction models improves the estimates.
PMCID: PMC3374026  PMID: 22692650
13.  Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data 
Holmes, Michael V | Dale, Caroline E | Zuccolo, Luisa | Silverwood, Richard J | Guo, Yiran | Ye, Zheng | Prieto-Merino, David | Dehghan, Abbas | Trompet, Stella | Wong, Andrew | Cavadino, Alana | Drogan, Dagmar | Padmanabhan, Sandosh | Li, Shanshan | Yesupriya, Ajay | Leusink, Maarten | Sundstrom, Johan | Hubacek, Jaroslav A | Pikhart, Hynek | Swerdlow, Daniel I | Panayiotou, Andrie G | Borinskaya, Svetlana A | Finan, Chris | Shah, Sonia | Kuchenbaecker, Karoline B | Shah, Tina | Engmann, Jorgen | Folkersen, Lasse | Eriksson, Per | Ricceri, Fulvio | Melander, Olle | Sacerdote, Carlotta | Gamble, Dale M | Rayaprolu, Sruti | Ross, Owen A | McLachlan, Stela | Vikhireva, Olga | Sluijs, Ivonne | Scott, Robert A | Adamkova, Vera | Flicker, Leon | van Bockxmeer, Frank M | Power, Christine | Marques-Vidal, Pedro | Meade, Tom | Marmot, Michael G | Ferro, Jose M | Paulos-Pinheiro, Sofia | Humphries, Steve E | Talmud, Philippa J | Leach, Irene Mateo | Verweij, Niek | Linneberg, Allan | Skaaby, Tea | Doevendans, Pieter A | Cramer, Maarten J | van der Harst, Pim | Klungel, Olaf H | Dowling, Nicole F | Dominiczak, Anna F | Kumari, Meena | Nicolaides, Andrew N | Weikert, Cornelia | Boeing, Heiner | Ebrahim, Shah | Gaunt, Tom R | Price, Jackie F | Lannfelt, Lars | Peasey, Anne | Kubinova, Ruzena | Pajak, Andrzej | Malyutina, Sofia | Voevoda, Mikhail I | Tamosiunas, Abdonas | Maitland-van der Zee, Anke H | Norman, Paul E | Hankey, Graeme J | Bergmann, Manuela M | Hofman, Albert | Franco, Oscar H | Cooper, Jackie | Palmen, Jutta | Spiering, Wilko | de Jong, Pim A | Kuh, Diana | Hardy, Rebecca | Uitterlinden, Andre G | Ikram, M Arfan | Ford, Ian | Hyppönen, Elina | Almeida, Osvaldo P | Wareham, Nicholas J | Khaw, Kay-Tee | Hamsten, Anders | Husemoen, Lise Lotte N | Tjønneland, Anne | Tolstrup, Janne S | Rimm, Eric | Beulens, Joline W J | Verschuren, W M Monique | Onland-Moret, N Charlotte | Hofker, Marten H | Wannamethee, S Goya | Whincup, Peter H | Morris, Richard | Vicente, Astrid M | Watkins, Hugh | Farrall, Martin | Jukema, J Wouter | Meschia, James | Cupples, L Adrienne | Sharp, Stephen J | Fornage, Myriam | Kooperberg, Charles | LaCroix, Andrea Z | Dai, James Y | Lanktree, Matthew B | Siscovick, David S | Jorgenson, Eric | Spring, Bonnie | Coresh, Josef | Li, Yun R | Buxbaum, Sarah G | Schreiner, Pamela J | Ellison, R Curtis | Tsai, Michael Y | Patel, Sanjay R | Redline, Susan | Johnson, Andrew D | Hoogeveen, Ron C | Hakonarson, Hakon | Rotter, Jerome I | Boerwinkle, Eric | de Bakker, Paul I W | Kivimaki, Mika | Asselbergs, Folkert W | Sattar, Naveed | Lawlor, Debbie A | Whittaker, John | Davey Smith, George | Mukamal, Kenneth | Psaty, Bruce M | Wilson, James G | Lange, Leslie A | Hamidovic, Ajna | Hingorani, Aroon D | Nordestgaard, Børge G | Bobak, Martin | Leon, David A | Langenberg, Claudia | Palmer, Tom M | Reiner, Alex P | Keating, Brendan J | Dudbridge, Frank | Casas, Juan P
Objective To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.
Design Mendelian randomisation meta-analysis of 56 epidemiological studies.
Participants 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.
Main outcome measures Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.
Results Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (−0.88 (−1.19 to −0.56) mm Hg), interleukin-6 levels (−5.2% (−7.8 to −2.4%)), waist circumference (−0.3 (−0.6 to −0.1) cm), and body mass index (−0.17 (−0.24 to −0.10) kg/m2). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).
Conclusions Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.
PMCID: PMC4091648  PMID: 25011450

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