Publications by authors named "Amal Muthumala"

20 Publications

  • Page 1 of 1

Electrocardiographic predictors of successful resynchronization of left bundle branch block by His bundle pacing.

J Cardiovasc Electrophysiol 2021 Feb 4;32(2):428-438. Epub 2021 Jan 4.

National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.

Background: His bundle pacing (HBP) is an alternative to biventricular pacing (BVP) for delivering cardiac resynchronization therapy (CRT) in patients with heart failure and left bundle branch block (LBBB). It is not known whether ventricular activation times and patterns achieved by HBP are equivalent to intact conduction systems and not all patients with LBBB are resynchronized by HBP.

Objective: To compare activation times and patterns of His-CRT with BVP-CRT, LBBB and intact conduction systems.

Methods: In patients with LBBB, noninvasive epicardial mapping (ECG imaging) was performed during BVP and temporary HBP. Intrinsic activation was mapped in all subjects. Left ventricular activation times (LVAT) were measured and epicardial propagation mapping (EPM) was performed, to visualize epicardial wavefronts. Normal activation pattern and a normal LVAT range were determined from normal subjects.

Results: Forty-five patients were included, 24 with LBBB and LV impairment, and 21 with normal 12-lead ECG and LV function. In 87.5% of patients with LBBB, His-CRT successfully shortened LVAT by ≥10 ms. In 33.3%, His-CRT resulted in complete ventricular resynchronization, with activation times and patterns indistinguishable from normal subjects. EPM identified propagation discontinuity artifacts in 83% of patients with LBBB. This was the best predictor of whether successful resynchronization was achieved by HBP (logarithmic odds ratio, 2.19; 95% confidence interval, 0.07-4.31; p = .04).

Conclusion: Noninvasive electrocardiographic mapping appears to identify patients whose LBBB can be resynchronized by HBP. In contrast to BVP, His-CRT may deliver the maximum potential ventricular resynchronization, returning activation times, and patterns to those seen in normal hearts.
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http://dx.doi.org/10.1111/jce.14845DOI Listing
February 2021

Post-operative cardiac implantable electronic devices in patients undergoing cardiac surgery: a contemporary experience.

Europace 2021 Jan;23(1):104-112

Cardiac Research Department, Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, 1 St Martin's Le Grand, West Smithfield, London EC1A 7BE, UK.

Aims: Optimum timing of pacemaker implantation following cardiac surgery is a clinical challenge. European and American guidelines recommend observation, to assess recovery of atrioventricular block (AVB) (up to 7 days) and sinus node (5 days to weeks) after cardiac surgery. This study aims to determine rates of cardiac implantable electronic devices (CIEDs) implants post-surgery at a high-volume tertiary centre over 3 years. Implant timing, patient characteristics and outcomes at 6 months including pacemaker utilization were assessed.

Methods And Results: All cardiac operations (n = 5950) were screened for CIED implantation following surgery, during the same admission, from 2015 to 2018. Data collection included patient, operative, and device characteristics; pacing utilization and complications at 6 months. A total of 250 (4.2%) implants occurred; 232 (3.9%) for bradycardia. Advanced age, infective endocarditis, left ventricle systolic impairment, and valve surgery were independent predictors for CIED implants (P < 0.0001). Relative risk (RR) of CIED implants and proportion of AVB increased with valve numbers operated (single-triple) vs. non-valve surgery: RR 5.4 (95% CI 3.9-7.6)-21.0 (11.4-38.9) CIEDs. Follow-up pacing utilization data were available in 91%. Significant utilization occurred in 82% and underutilization (<1% A and V paced) in 18%. There were no significant differences comparing utilization rates in early (≤day 5 post-operatively) vs. late implants (P = 0.55).

Conclusion: Multi-valve surgery has a particularly high incidence of CIED implants (14.9% double, 25.6% triple valve). Age, left ventricle systolic impairment, endocarditis, and valve surgery were independent predictors of CIED implants. Device underutilization was infrequent and uninfluenced by implant timing. Early implantation (≤5 days) should be considered in AVB post-multi-valve surgery.
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http://dx.doi.org/10.1093/europace/euaa241DOI Listing
January 2021

Clinical outcomes of His-Purkinje conduction system pacing.

Pacing Clin Electrophysiol 2021 01 7;44(1):5-14. Epub 2020 Sep 7.

Geisinger Heart Institute, Wilkes-Barre, Pennsylvania.

His-Purkinje conduction system pacing (HPCSP) in the form of His bundle pacing (HBP) and left bundle branch pacing (LBBP) allows normal left ventricular activation, thereby preventing the adverse consequences of right ventricular pacing. HBP has been established for several years with centers from China, Europe, and North America reporting their experience. There is international guidance as to how to implant such systems with the differing patterns of His bundle capture clearly described. LBBP is a more recent innovation with potential advantages including improved pacing parameters. HPCSP has been extensively studied in a variety of indications including cardiac resynchronization therapy, atrioventricular node ablation, and bradycardia pacing. This review will focus on the clinical outcomes of HPCSP including mortality and morbidity of heart failure hospitalization and symptoms.
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http://dx.doi.org/10.1111/pace.14050DOI Listing
January 2021

His-Purkinje conduction system pacing and atrioventricular node ablation.

Herzschrittmacherther Elektrophysiol 2020 Jun 6;31(2):117-123. Epub 2020 May 6.

Geisinger Commonwealth School of Medicine, Director, Cardiac Electrophysiology, Geisinger Heart Institute, MC 36-10, Mountain Blvd, 1000, Wilkes-Barre, PA, USA.

His-Purkinje conduction system pacing (HPCSP) in the form of His bundle pacing and left bundle branch pacing allows normal ventricular activation, thereby preventing the adverse consequences of right ventricular pacing. One potential area where HPCSP could be used is in the field of atrioventricular (AV) node ablation in patients with atrial fibrillation refractory to medical therapy and/or catheter ablation. His bundle pacing has been established for several years, with centres from North America, Europe and China publishing their experience. The differing patterns of His bundle capture are clearly described with established guidance as to how to implant such systems. Left bundle branch pacing has only recently been reported, but there are several advantages with better pacing parameters and lower risk of threshold change after AV node ablation. Six studies have been identified in the literature which describe the experience of His bundle pacing in patients requiring AV node ablation. Overall the results are positive and favour this new technique; however, they are limited by low numbers of patients and non-randomised study design. An observational study was recently published demonstrating better outcomes with left bundle branch pacing in a small number of patients with left ventricular dysfunction and atrial fibrillation that underwent AV node ablation. HPCSP has the potential to be the primary pacing modality in patients with atrial fibrillation requiring AV node ablation. However, it is essential that this is confirmed in large randomised clinical trials.
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http://dx.doi.org/10.1007/s00399-020-00679-7DOI Listing
June 2020

Non-vitamin K oral anticoagulants at the time of cardiac rhythm device surgery: A systematic review and meta-analysis.

Thromb Res 2020 04 12;188:90-96. Epub 2020 Feb 12.

Barts Heart Centre, St. Bartholomew's Hospital, London, United Kingdom.

Introduction: Use of non-vitamin K oral anticoagulants (NOACs) has rapidly increased worldwide. We aimed to systematically assess the available evidence regarding the safety and efficacy of NOACs in patients undergoing cardiac implantable electronic device (CIED) surgery.

Methods: We performed a systematic literature search. Eligible randomised controlled trials and cohort studies were included. The primary outcome measures were clinically significant device-pocket haematoma and thromboembolic events.

Results: A total of 12 studies were included, equating to 2120 patients. The separate pooling of rate of events showed a low incidence of clinically significant device-pocket haematoma, although numerically higher in patients on continued (1.5%; CI0.8-3.0) versus interrupted NOAC (0.9%; CI0.5-1.7). The rate of any device-pocket haematoma was numerically higher in the continued versus interrupted NOAC group (5.4%; CI3.8-7.7 versus 2.4%; CI1.8-3.3). The incidence of thromboembolic events (0.4%; CI0.2-0.8) was low and comparable. From a meta-analysis of 3 studies (equating to 773 subjects) allowing for a comparison of continued versus interrupted NOAC, we found no significant difference between the 2 strategies in terms of clinically significant pocket haematoma (RR1.14; CI0.43-3.06, p = 0.79), thromboembolic complications (RR1.03; CI0.06-16.37, p = 0.98), and any pocket haematoma (RR1.19; CI0.65-2.20, p = 0.57).

Conclusion: Use of NOACs at the time of CIEDs surgery appears to be safe, and either strategy of peri-procedure continuation or interruption might be reasonable. However, continuation of NOAC seems to be associated with a numerically higher rate of bleeding complications. Certainty of the evidence is low, and further studies are required to confirm these findings.
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http://dx.doi.org/10.1016/j.thromres.2020.02.007DOI Listing
April 2020

Predictors of left ventricular remodelling in patients with dilated cardiomyopathy - a cardiovascular magnetic resonance study.

Eur J Heart Fail 2020 07 13;22(7):1160-1170. Epub 2020 Feb 13.

National Heart Lung Institute, Imperial College London, UK.

Aims: There is an important need for better biomarkers to predict left ventricular (LV) remodelling in dilated cardiomyopathy (DCM). We undertook a comprehensive assessment of cardiac structure and myocardial composition to determine predictors of remodelling.

Methods And Results: Prospective study of patients with recent-onset DCM with cardiovascular magnetic resonance (CMR) assessment of ventricular structure and function, extracellular volume (T1 mapping), myocardial strain, myocardial scar (late gadolinium enhancement) and contractile reserve (dobutamine stress). Regression analyses were used to evaluate predictors of change in LV ejection fraction (LVEF) over 12 months. We evaluated 56 participants (34 DCM patients, median LVEF 43%; 22 controls). Absolute LV contractile reserve predicted change in LVEF (1% increase associated with 0.4% increase in LVEF at 12 months, P = 0.02). Baseline myocardial strain (P = 0.39 global longitudinal strain), interstitial myocardial fibrosis (P = 0.41), replacement myocardial fibrosis (P = 0.25), and right ventricular contractile reserve (P = 0.17) were not associated with LV reverse remodelling. There was a poor correlation between contractile reserve and either LV extracellular volume fraction (r = -0.22, P = 0.23) or baseline LVEF (r = 0.07, P = 0.62). Men were more likely to experience adverse LV remodelling (P = 0.01) but age (P = 0.88) and disease-modifying heart failure medication (beta-blocker, P = 0.28; angiotensin-converting enzyme inhibitor, P = 0.92) did not predict follow-up LVEF.

Conclusions: Substantial recovery of LV function occurs within 12 months in most patients with recent-onset DCM. Women had the greatest improvement in LVEF. A low LV contractile reserve measured by dobutamine stress CMR appears to identify patients whose LVEF is less likely to recover.
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http://dx.doi.org/10.1002/ejhf.1734DOI Listing
July 2020

Rupture of mitral valve papillary muscle: a rare complication following myocardial infarction.

BMJ Case Rep 2020 Jan 15;13(1). Epub 2020 Jan 15.

Cardiology, North Middlesex University Hospital, London, UK.

Here we present a rare clinical presentation of papillary muscle rupture in a 55-year-old man who presented to accident and emergency department with chest pain and was diagnosed as having had a non-ST elevation myocardial infarction. During the admission, he developed papillary muscle rupture due to the myocardial infarction resulting in acute mitral regurgitation. This caused significant haemodynamic compromise needing emergency admission to the intensive care unit and eventually surgery to replace the valve.
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http://dx.doi.org/10.1136/bcr-2019-232626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021130PMC
January 2020

A Novel Quadripolar Active Fixation Left-Ventricular Pacing Lead for Cardiac Resynchronization Therapy: Initial United Kingdom Experience.

JACC Clin Electrophysiol 2019 09 31;5(9):1028-1035. Epub 2019 Jul 31.

James Cook University Hospital, Middlesbrough, United Kingdom.

Objectives: This study sought to assess immediate and short-term performance of the Medtronic Attain Stability Quadripolar 4798 lead (Medtronic, Dublin, Ireland).

Background: Cardiac resynchronization therapy (CRT) is an established treatment for appropriately selected patients with left ventricular (LV) systolic dysfunction. The most common reason for failure to implant a lead is the lack of a suitable epicardial vein, due either to an absent vessel in the target site, an unacceptably high threshold, lead instability, phrenic nerve stimulation, or a combination of reasons. In August 2017, a novel quadripolar active fixation LV lead (Medtronic) was released. This paper reports the initial clinical experience with lead implantation and specifically immediate and short-term pacing parameters across 3 United Kingdom centers.

Methods: Consecutive patients eligible for CRT were deemed suitable for this lead. Immediate and short-term lead performance data regarding LV threshold, impedance, and displacement rates were collected at standard pacing checks (1 day, 5 weeks, 3 months, and 9 months post-implantation).

Results: CRT using this lead was attempted in 82 cases and was successful in 81 cases (98.8%). LV thresholds and impedance levels were 1.22 ± 0.75 V and 737 ± 319 Ω at implantation; 1.16 ± 0.71 V and 597 ± 218 Ω at day 1; 1.02 ± 0.48 V and 579 ± 148 Ω at week 6; 0.98 ± 0.49 V and 569 ± 133 Ω at 3 months; and 1.06 ± 0.48 V and 570 ± 140 Ω at 9 months. As of the publication of this paper, no LV lead has been displaced.

Conclusions: CRT using the Medtronic lead was successful in more than 98% of the patients. Short-to-medium-term data regarding lead performance and stability were excellent, with zero displacements as of the publication of this paper.
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http://dx.doi.org/10.1016/j.jacep.2019.05.005DOI Listing
September 2019

Full blood count as potential predictor of outcomes in patients undergoing cardiac resynchronization therapy.

Sci Rep 2019 09 10;9(1):13016. Epub 2019 Sep 10.

Electrophysiology Department, Barts Heart Centre, St. Bartholomew's Hospital, London, United Kingdom.

Almost a third of patients fulfilling current guidelines criteria have suboptimal responses following cardiac resynchronization therapy (CRT). Circulating biomarkers may help identify these patients. We aimed to assess the predictive role of full blood count (FBC) parameters in prognosis of heart failure (HF) patients undergoing CRT device implantation. We enrolled 612 consecutive CRT patients and FBC was measured within 24 hours prior to implantation. The follow-up period was a median of 1652 days (IQR: 837-2612). The study endpoints were i) composite of all-cause mortality or transplant, and ii) reverse left ventricular (LV) remodeling. On multivariate analysis [hazard ratio (HR), 95% confidence interval (CI)] only red cell count (RCC) (p = 0.004), red cell distribution width (RDW) (p < 0.001), percentage of lymphocytes (p = 0.03) and platelet count (p < 0.001) predicted all-cause mortality. Interestingly, RDW (p = 0.004) and platelet count (p = 0.008) were independent predictors of reverse LV remodeling. This is the first powered single-centre study to demonstrate that RDW and platelet count are independent predictors of long-term all-cause mortality and/or heart transplant in CRT patients. Further studies, on the role of these parameters in enhancing patient selection for CRT implantation should be conducted to confirm our findings.
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http://dx.doi.org/10.1038/s41598-019-49659-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736835PMC
September 2019

Transient rise in His-lead threshold due to acute myocardial infarction.

Pacing Clin Electrophysiol 2019 06 15;42(6):754-757. Epub 2019 Feb 15.

Barts Heart Centre, West Smithfield, London, England.

An 85-year-old male was admitted to our center with a non-ST elevation myocardial infarction. The patient had a dual-chamber pacemaker in situ with an atrial and His lead. A transient increase in His threshold and loss of nonselective capture occurred at the presentation of right coronary artery infarction, peaking during rotational atherectomy therapy causing loss of capture and complete atrioventricular block. A follow-up interrogation, 2 weeks postrevascularization, showed a return to a normal nonselective capture morphology and threshold measurements. Physicians should be aware of this complication in patients with His leads, particularly those with a history of coronary artery disease.
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http://dx.doi.org/10.1111/pace.13612DOI Listing
June 2019

His Resynchronization Versus Biventricular Pacing in Patients With Heart Failure and Left Bundle Branch Block.

J Am Coll Cardiol 2018 12;72(24):3112-3122

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Background: His bundle pacing is a new method for delivering cardiac resynchronization therapy (CRT).

Objectives: The authors performed a head-to-head, high-precision, acute crossover comparison between His bundle pacing and conventional biventricular CRT, measuring effects on ventricular activation and acute hemodynamic function.

Methods: Patients with heart failure and left bundle branch block referred for conventional biventricular CRT were recruited. Using noninvasive epicardial electrocardiographic imaging, the authors identified patients in whom His bundle pacing shortened left ventricular activation time. In these patients, the authors compared the hemodynamic effects of His bundle pacing against biventricular pacing using a high-multiple repeated alternation protocol to minimize the effect of noise, as well as comparing effects on ventricular activation.

Results: In 18 of 23 patients, left ventricular activation time was significantly shortened by His bundle pacing. Seventeen patients had a complete electromechanical dataset. In them, His bundle pacing was more effective at delivering ventricular resynchronization than biventricular pacing: greater reduction in QRS duration (-18.6 ms; 95% confidence interval [CI]: -31.6 to -5.7 ms; p = 0.007), left ventricular activation time (-26 ms; 95% CI: -41 to -21 ms; p = 0.002), and left ventricular dyssynchrony index (-11.2 ms; 95% CI: -16.8 to -5.6 ms; p < 0.001). His bundle pacing also produced a greater acute hemodynamic response (4.6 mm Hg; 95% CI: 0.2 to 9.1 mm Hg; p = 0.04). The incremental activation time reduction with His bundle pacing over biventricular pacing correlated with the incremental hemodynamic improvement with His bundle pacing over biventricular pacing (R = 0.70; p = 0.04).

Conclusions: His resynchronization delivers better ventricular resynchronization, and greater improvement in hemodynamic parameters, than biventricular pacing.
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http://dx.doi.org/10.1016/j.jacc.2018.09.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290113PMC
December 2018

Rationale and design of the randomized multicentre His Optimized Pacing Evaluated for Heart Failure (HOPE-HF) trial.

ESC Heart Fail 2018 10 9;5(5):965-976. Epub 2018 Jul 9.

Imperial College London, London, UK.

Aims: In patients with heart failure and a pathologically prolonged PR interval, left ventricular (LV) filling can be improved by shortening atrioventricular delay using His-bundle pacing. His-bundle pacing delivers physiological ventricular activation and has been shown to improve acute haemodynamic function in this group of patients. In the HOPE-HF (His Optimized Pacing Evaluated for Heart Failure) trial, we are investigating whether these acute haemodynamic improvements translate into improvements in exercise capacity and heart failure symptoms.

Methods And Results: This multicentre, double-blind, randomized, crossover study aims to randomize 160 patients with PR prolongation (≥200 ms), LV impairment (EF ≤ 40%), and either narrow QRS (≤140 ms) or right bundle branch block. All patients receive a cardiac device with leads positioned in the right atrium and the His bundle. Eligible patients also receive a defibrillator lead. Those not eligible for implantable cardioverter defibrillator have a backup pacing lead positioned in an LV branch of the coronary sinus. Patients are allocated in random order to 6 months of (i) haemodynamically optimized dual chamber His-bundle pacing and (ii) backup pacing only, using the non-His ventricular lead. The primary endpoint is change in exercise capacity assessed by peak oxygen uptake. Secondary endpoints include change in ejection fraction, quality of life scores, B-type natriuretic peptide, daily patient activity levels, and safety and feasibility assessments of His-bundle pacing.

Conclusions: Hope-HF aims to determine whether correcting PR prolongation in patients with heart failure and narrow QRS or right bundle branch block using haemodynamically optimized dual chamber His-bundle pacing improves exercise capacity and symptoms. We aim to complete recruitment by the end of 2018 and report in 2020.
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http://dx.doi.org/10.1002/ehf2.12315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165934PMC
October 2018

A case of difficult RV lead placement.

Heart 2014 Mar 27;100(5):434-5, 439. Epub 2013 Dec 27.

Department of Cardiology, Liverpool Heart and Chest Hospital, , Liverpool, UK.

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http://dx.doi.org/10.1136/heartjnl-2013-305263DOI Listing
March 2014

Overdrive pacing using an ICD with an unexpected AV response: what is the cause?

Pacing Clin Electrophysiol 2013 Aug 28;36(8):1027-9. Epub 2013 Jan 28.

Department of Cardiology, Oxford University Hospitals NHS Trust, Oxford, UK.

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http://dx.doi.org/10.1111/pace.12083DOI Listing
August 2013

Role of beta adrenergic receptor polymorphisms in heart failure: systematic review and meta-analysis.

Eur J Heart Fail 2008 Jan 26;10(1):3-13. Epub 2007 Dec 26.

Centre for Cardiovascular Genetics, Rayne Institute, Royal Free and University College Medical School, London WC1E 6JF, UK.

Heart Failure (HF) is a common disorder associated with substantial morbidity and mortality. beta adrenergic receptors (betaAR) are the primary pathway through which cardiac function is influenced. Chronic beta(1)AR activation is implicated in the pathogenesis of HF and betaAR blockade improves survival in left ventricular systolic dysfunction. Common functional polymorphisms in beta adrenergic receptor genes (ADRB) have been associated with HF phenotypes, and with pharmacogenetic interaction with beta adrenergic receptor blockers (beta blockers). However, these associations have not been consistently replicated. The evidence for ADRB variant involvement in pathogenesis, progression and response to beta blockers in HF is reviewed. In addition, a meta-analysis of three studies analysing the effect of ADRB1 Arg389Gly polymorphism on left ventricular remodelling with the use of beta blockers, demonstrating a 5% improvement in left ventricular ejection fraction in Arg389 homozygotes, is presented. There is now accumulating molecular evidence for a different functional response to beta blockers associated with this polymorphism. In the future, confirmed genotypic associations may enable patients to be identified who are either at greater risk of developing HF, whose HF may rapidly progress, or who are unlikely to benefit from beta blockers, and such patients may benefit from targeted aggressive therapy.
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http://dx.doi.org/10.1016/j.ejheart.2007.11.008DOI Listing
January 2008

Chronic heart failure and chronic obstructive pulmonary disease: one problem, one solution?

Authors:
Amal Muthumala

Int J Cardiol 2008 Mar 26;125(1):1-3. Epub 2007 Nov 26.

Chronic heart failure and chronic obstructive pulmonary disease are both increasing in prevalence throughout the developed world. Despite new therapies especially for chronic heart failure, morbidity and mortality rates for both conditions remain high. This editorial highlights the skeletal myopathy that has been recognised in both diseases, and its central role in exercise limitation. Exercise training has been shown to benefit the myopathy, functional capacity and also survival, again in both conditions. Exercise training is now established in the guidelines for both diseases in the developed world and some reasons are suggested why its implementation has so far been limited especially for heart failure. In view of its effectiveness as a therapy, the failure to apply these guidelines should be addressed.
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http://dx.doi.org/10.1016/j.ijcard.2007.07.160DOI Listing
March 2008

Is the influence of variation in the ACE gene on the prospective risk of Type 2 diabetes in middle-aged men modified by obesity?

Clin Sci (Lond) 2007 Dec;113(12):467-72

Centre For Cardiovascular Genetics, Royal Free and UCL Medical School, The Rayne Institute, 5 University Street, London WC1E 6JF, UK.

There is strong evidence for the presence of a functional renin-angiotensin system in diabetogenic tissues, and ACE (angiotensin-converting enzyme) inhibitors may improve glucose metabolism in those individuals at high risk of developing T2DM (Type 2 diabetes). In the present study, we tested the hypothesis that subjects with genetically lower plasma and tissue ACE activity, because of their ACE [I/D (insertion/deletion)] genotype, would have a lower risk of T2DM in 2642 healthy middle-aged Caucasian men (mean age, 56 years) followed-up for 15 years. Obesity was the strongest predictor of T2DM, with an HR (95% CI) [hazard ratio (95% confidence interval)] of 3.74 (2.66-5.26) (P<0.0001). Overall there was no association between ACE genotype (II homozygotes, n=623; and D allele carriers, n=2019) and risk of T2DM, and although in lean men there was no genotype difference in risk in D allele carriers compared with II homozygotes [adjusted HR=0.75 (95% CI, 0.46-1.22)], in obese (body mass index >30 kg/m(2)) men the risk of T2DM was higher [adjusted HR=4.26 (95% CI, 1.30-13.93)] with a genotype-obesity interaction of P=0.01. A similar pattern of risk was seen by re-analysis of a previously published case-control study, where D allele carriers had a non-significant 1.30 (0.97-1.74)-fold higher risk of developing T2DM than II homozygotes when non-obese, but a 1.79 (1.17-2.72) (P=0.007)-fold higher risk when obese. Further prospective studies are needed to confirm these findings. The ACE D allele may worsen glucose metabolism, which could raise the prospective T2DM risk in obese men, but not in lean men. In obesity, adipose tissue undergoes inflammatory infiltration and the subsequent higher levels of pro-inflammatory angiotensin II may explain this association.
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http://dx.doi.org/10.1042/CS20070158DOI Listing
December 2007

Angiotensin-converting enzyme genotype interacts with systolic blood pressure to determine coronary heart disease risk in healthy middle-aged men.

Hypertension 2007 Aug 11;50(2):348-53. Epub 2007 Jun 11.

Centre for Cardiovascular Genetics, Royal Free and UCL Medical School, The Rayne Institute, London, UK.

The impact of the ACE I/D polymorphism on coronary heart disease (CHD) risk is modest at most, however it may act as a modifier gene. ACE genotype was determined in 2711 healthy middle-aged men (mean age 56 years) followed for 15 years. No genotype-CHD risk association was found, but when analyzed by quartiles of systolic blood pressure (SBP), compared with II homozygotes, carriage of each additional D allele was protective at lower SBP, but in the highest quartile (SBP >150 mm Hg) conferred almost 1.5 times the risk for CHD (genotype interaction P=0.003). When SBP was analyzed as a continuous variable, again a highly significant association was seen, with the hazard ratio ([95% CI]) for a 1 SD increase in SBP being 0.90 [0.70 to 1.15] for IIs and 1.40 [1.21 to 1.61] for ID/DD (genotype SBP interaction P=0.002). The D allele was protective against CHD at lower SBP but would overtake the II risk at higher SBP. In hypertension, the proinflammatory or prohypertrophic properties of angiotensin II may explain this association. The LPL S447X polymorphism also impacts on CHD risk through interaction with hypertension, and there was an additive action of these 2 polymorphisms and SBP on CHD risk (hazard ratio for 1 SD increase in SBP for combined genotypes 1.78 [1.30 to 2.45]). Thus in the presence of hypertension, common variation in "modifier" genes confers significant CHD risk.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.086843DOI Listing
August 2007