Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy

doi:10.1016/0140-6736(93)92061-W

The Lancet

Volume 342, Issue 8879, 30 October 1993, Pages 1073-1075

https://doi.org/10.1016/0140-6736(93)92061-W Get rights and content

Abstract

Summary

Polymorphism in the angiotensin-converting enzyme (ACE) gene has been shown to correlate with circulating ACE concentrations, and also to be an independent risk factor for the development of myocardial infarction, particularly in men thought to be at low risk by standard criteria.

We determined the genotypes of individuals with end-stage heart failure due to either ischaemic dilated cardiomyopathy (102) or idiopathic dilated cardiomyopathy (112) and compared these to organ donors with normally functioning hearts (79). Genotypes were determined by the polymerase chain reaction with oligonucleotide primers flanking the polymorphic region in intron 16 of the ACE gene to amplify template DNA isolated from patients.

Compared with the DD frequency in the control population, the frequency of the ACE DD genotype was 48% higher in individuals with idiopathic dilated cardiomyopathy (p=0·008) and 63% higher in subjects with ischaemic cardiomyopathy (p=0·008), suggesting that an ACE gene variant may contribute to the pathogenesis of both types of cardiomyopathy.

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Cited by (451)

Insertion/deletion polymorphism of ACE gene in females with peripartum cardiomyopathy: A case-control study
2018, Indian Heart Journal
The role of polymorphism of Angiotensin converting enzyme (ACE) gene and ACE activity in etiopathogenesis, prognosis, and many other clinical parameters in the various form of the cardiovascular disease has been established to some degree of certainty. The pathophysiology of Peripartum cardiomyopathy (PPCM) remains an area of active research. The main aim of our study was to see pattern of ACE- Insertion/Deletion (I/D) allele in PPCM and its implications on left ventricular performance indices.
This single-center case-control study included 45 cases and 70 controls. The diagnosis of PPCM was established clinically and echocardiographically. ACE genotyping was done by polymerase chain reaction (PCR) method in all subjects.
The II, ID, and DD genotype was present in 16, 18 and 11 of subjects with PPCM and 48, 19 and 3 of controls respectively. The odds ratio for ACE-II genotype in cases vs. controls was 0.253 (95% CI = 0.114–0.558; p = 0.007), for that of II genotype was 1.93 (95% CI = 0.86–4.3; p = 0.107) and for DD genotype was 7.225 (95% CI; 1.88–27.6; p = 0.0039). Overall frequency of D allele in cases was significantly higher than controls (odds = 4.25; 95% CI = 2.01–6.7; p = 0.0001). Moreover, ejection fraction, left ventricular volume and linear dimensions were worse in patients with DD genotype.
ACE DD genotype and overall frequency of D allele is significantly higher in patients with PPCM. Also, the presence of DD genotype is associated with worse systolic performance indices measured echocardiographically.
Cardiac involvement in myotonic dystrophy: The role of troponins and N-terminal pro B-type natriuretic peptide
2017, Atherosclerosis
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are dominant inherited muscular dystrophies with multiple systemic involvement, often producing cardiac injury. This study sought to determine the clinical significance of elevated high sensitivity cardiac troponin T and I (hs-cTnT and hs-cTnI), and N-terminal pro B-type natriuretic peptide (NT-pro-BNP) in this population.
Sixty DM patients (35 men and 25 women; mean age: 45.1 years, range: 12–73 years) underwent clinical cardiac investigations and measurements of serum hs-cTnT, hs-cTnI, creatine kinase (CK), and NT-proBNP. Left ventricular (LV) ejection fraction (EF) was assessed by echocardiography.
Genetic analysis revealed that 46 of the 60 patients were DM1, and 14 DM2. Blood measurements showed persistent elevation of hs-cTnT and CK in 55/60 DM patients (91.73%). In contrast, hs-cTnI values were persistently normal throughout the study. Only 2 patients showed an EF <50%, being the overall range of this population between 40% and 79%. We found ECG abnormalities in 19 patients. Of these patients, 13 showed first or second-degree atrio ventricular (AV) blocks (PR interval ≥ 200 ms), 4 showed a left bundle branch block (LBBB) prolonged (QRS duration ≥120 ms), and 2 had an incomplete bundle branch block (QRS duration between 110 and 119 ms). After excluding patients with EF <50%, NT-pro-BNP measurement > 125 pg/mL was an independent predictor of ECG abnormalities.
NT-pro-BNP levels may be considered to be used clinically to identify DM patients at increased risk of developing myocardial conduction abnormalities.
Influence of Angiotensin-converting Enzyme Genetic Polymorphism on Late Renal Dysfunction after Adult-to-adult Living-donor Liver Transplantation
2016, Transplantation Proceedings
Citation Excerpt :
However, the incidence of D/D type in their population was 20.3%, which is higher than the 10.9% in our study. It is known that serum concentrations of ACE in the D/D type [8] are increased as compared with the other genotypes, and furthermore the incidences of various circulatory diseases and renal failures are significantly higher in the D/D type [9,10]. Therefore, we elucidated the risk factors of LRD after LDLT, focusing on ACE genetic polymorphism in the present study.
Late renal dysfunction (LRD) is known to be one of the most important complications to affect long-term outcome after living-donor liver transplantation (LDLT). The relationship between angiotensin-converting enzyme insertion (I)/deletion (D) gene polymorphism and renal function after LDLT are still unknown. The aim of this study was to elucidate the risk factors for LRD after LDLT, focusing on ACE gene polymorphism.
Among the 94 recipients who underwent adult-to-adult LDLT between March 2002 and September 2009, the total number of subjects who survived more than 1 year after LDLT and in whom angiotensin-converting enzyme genotype could be measured was 64. LRD was defined as estimated glomerular filtration rate level less than 60 mL/min/1.73 m² at any point after 1 year from undergoing LDLT.
LRD was found in 24 patients (37.5%). The incidence of LRD was significantly higher in D/D type than in I/I or I/D type: 85.7% (6/7) vs. 42.1% (8/19), 35.7% (10/38) (P = .010). Preoperative estimated glomerular filtration rate was significantly lower in D/D type than in I/I, I/D types, and postoperatively they were significantly lower in D/D type at 2, 3, and 4 years after LDLT. By multivariate analysis, age and hypertension were the independent risk factors for LRD. The 10-year survival rate was much lower in the recipients with LRD than in those without LRD at 66.7% versus 87.5%, respectively (P = .053).
In conclusion, age and hypertension were determined as significant independent risk factors for LRD after adult-to-adult LDLT, and the recipients with D/D genotype should be strictly cared for the development of LRD.
Heart Failure in Non-Caucasians, Women, and Older Adults: A White Paper on Special Populations from the Heart Failure Society of America Guideline Committee
2015, Journal of Cardiac Failure
Citation Excerpt :
Polymorphisms in the angiotensin-converting enzyme (ACE) gene that influences response to spironolactone and affects ventricular remodeling have been well described, although their effect on remodeling and hypertension is controversial.26 The D/D phenotype has been shown to be associated with LVH, hypertension, and HF risk.27–29 In African Americans, the deletion allele appears to be associated with hypertension.30
The presentation, natural history, clinical outcomes, and response to therapy in patients with heart failure differ in some ways across populations. Women, older adults, and non-Caucasian racial or ethnic groups compose a substantial proportion of the overall heart failure population, but they have typically been underrepresented in clinical trials. As a result, uncertainty exists about the efficacy of some guideline-directed medical therapies and devices in specific populations, which may result in the under- or overtreatment of these patients. Even when guideline-based treatments are prescribed, socioeconomic, physical, or psychologic factors may affect non-Caucasian and older adult patient groups to a different extent and affect the application, effectiveness, and tolerability of these therapies. Individualized therapy based on tailored biology (genetics, proteomics, metabolomics), socioeconomic and cultural considerations, and individual goals and preferences may be the optimal approach for managing diverse patients. This comprehensive approach to personalized medicine is evolving, but in the interim, the scientific community should continue efforts focused on intensifying research in special populations, prescribing guideline-directed medical therapy unless contraindicated, and implementing evidence-based strategies including patient and family education and multidisciplinary team care in the management of patients.
Biomarkers of activation of renin-angiotensin-aldosterone system in heart failure: How useful, how feasible?
2015, Clinica Chimica Acta
Citation Excerpt :
The DD polymorphism is associated with higher ACE activity, leading to higher angiotensin II levels [26]; in fact higher levels of angiotensin II have been associated with a worse outcome in heart failure patients [27]. A higher frequency of this polymorphism was observed in patients with ischemic or dilated cardiomyopathy [28], myocardial infarction [29,30], and various other cardiomyopathies [31]. As the response of ACE DD patients to the ACE inhibitor therapy did not statistically differ from that of ID and II patients, there was a statistical relevant difference on the response to the beta-blocker therapy [32,33]; in fact, not only ACE DD patients did show a better response to this treatment, but the lack of it was associated with an increased transplant need and a poorer transplant-free survival [33].
Renin-angiotensin-aldosterone system (RAAS), participated by kidney, liver, vascular endothelium, and adrenal cortex, and counter-regulated by cardiac endocrine function, is a complex endocrine system regulating systemic functions, such as body salt and water homeostasis and vasomotion, in order to allow the accomplishment of physiological tasks, such as orthostasis, physical and emotional stimuli, and to react towards the hemorrhagic insult, in tight conjunction with other neurohormonal axes, namely the sympathetic nervous system, the endothelin and vasopressin systems. The systemic as well as the tissue RAAS are also dedicated to promote tissue remodeling, particularly relevant after damage, when chronic activation may configure as a maladaptive response, leading to fibrosis, hypertrophy and apoptosis, and organ dysfunction. RAAS activation is a fingerprint of systemic arterial hypertension, kidney dysfunction, vascular atherosclerotic disease, and is definitely an hallmark of heart failure, which rapidly shifts from organ disease to a disorder of neurohormonal regulatory systems. Chronic RAAS activation is an indirect or direct target of most effective pharmacological treatments in heart failure, such as beta-blockers, inhibitors of angiotensin converting enzyme, angiotensin receptor blockers, direct renin inhibitors, and mineralocorticoid receptor blockers. Biomarkers of RAAS activation are available, with different feasibility and accuracy, such as plasma renin activity, renin, angiotensin II, and aldosterone, which all accompany the increasing clinical severity of heart failure disease, and are well recognized prognostic factors, even in patients with optimal therapy. Polymorphisms influencing the expression and activity of RAAS pathways have been recognized as clinically relevant biomarkers, likely influencing either the individual clinical phenotype, or the response to drugs. This solid, growing evidence strongly suggests the rationale for the use of biomarkers of the RAAS activation, as a guide to tailor individual therapy in the current practice, and their implementation as a rule-in marker for future trials on novel drugs in the heart failure setting.
A novel approach to drug development in heart failure: Towards personalized medicine
2014, Canadian Journal of Cardiology
Evidence-based treatment has succeeded in improving clinical outcomes in heart failure. Nevertheless, morbidity, mortality, and the economic burden associated with the syndrome remain unsatisfactorily high. Most landmark heart failure studies included broad study populations, and thus current recommendations dictate standardized, universal therapy. While most patients included in recent trials benefit from this background treatment, exceeding this already significant gain has proven to be a challenge. The early identification of responders and nonresponders to treatment could result in improved therapeutic effectiveness, while reduction of unnecessary exposure may limit harmful and unpleasant side effects. In this review, we examine the potential value of currently available information on differential responses to heart failure therapy—a first step toward personalized medicine in the management of heart failure.
Le traitement fondé sur des données probantes est parvenu à améliorer les résultats cliniques de l’insuffisance cardiaque. Néanmoins, la morbidité, la mortalité et le fardeau économique associés au syndrome demeurent trop élevés. Les études les plus marquantes sur l’insuffisance cardiaque incluaient de vastes populations, donc les recommandations actuelles dictent un traitement universel standardisé. Bien que la plupart des patients inclus dans les récents essais bénéficient de ce traitement de fond, le dépassement de ce gain déjà significatif s’est révélé difficile. L’identification précoce des patients qui répondent au traitement et de ceux qui n’y répondent pas permettrait d’améliorer l’efficacité thérapeutique, alors que la diminution de l’exposition inutile pourrait limiter les effets secondaires néfastes et désagréables. Dans cette revue, nous examinons la valeur potentielle des informations actuellement disponibles sur les effets différentiels du traitement de l’insuffisance cardiaque, une première étape vers la médecine personnalisée utile à la prise en charge de l’insuffisance cardiaque.

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ArticlesAngiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy

Abstract

Lancet

Am Heart J

Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure

N Engl J Med

Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction

N Engl J Med

Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction

Nature

Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels

Am J Hum Genet

Articles
Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy