Does angiotensin‐converting enzyme gene polymorphism affect blood pressure? Findings after 6 years of follow‐up in healthy subjects

BACKGROUND: There has been an increase in research into the association between angiotensin-converting enzyme (ACE) gene deletion polymorphism and cardiovascular disease, with conflicting results. The present prospective long-term study was conducted to evaluate whether the DD genotype could also be associated with a higher prevalence of hypertension in healthy subjects, over 6 years of follow-up. METHODS: Population: 684 healthy volunteers (aged, 25-55 years): normotensive and free of cardiovascular diseases, with acceptable echocardiographic window. All subjects had to have a normal electrocardiogram (ECG) and echocardiogram (ECHO) at entry. STUDY PROTOCOL: All subjects underwent a complete physical examination, 12-lead ECG and ECHO, and venous blood samples were drawn for DNA analysis and cholesterol. All subjects had a clinical evaluation each year for the 6 year duration of the study. RESULTS: All 684 subjects completed 6 years of follow-up. We identified three genetically distinct groups. The ACE-DD group (n=225, 80F/145M, mean age 43.4+/-7.6 years) had 42 hypertensive subjects (18.3%), 5 heart failure (HF) subjects and 6 subjects with acute coronary syndromes (ACS). There was no association between family history, smoking habit, hypercholesterolemia and events. The ACE-ID group (n=335, 116F/219M, mean age 43.6+/-7 years) had 16 hypertensive subjects (4.7%) and 3 subjects with ACS. The ACE-II group (n=124, 45F/79M, mean age 42.5+/-6.9 years) had 2 hypertensive subjects (1.6%) and 1 HF subject. The incidence of hypertension and cardiovascular events was significantly higher in the ACE-DD group (53 cases, 23%) than in the ACE-ID and ACE-II groups (20 and 3 cases, 5.9 and 2.4%, respectively), P=0.0001. The higher incidence of hypertension was observed in the older age groups (36-45 and 46-55 years) with ACE-DD and ACE-ID genotypes. CONCLUSION: Our data suggest that ACE-DD polymorphism is associated with a higher incidence of hypertension in baseline healthy subjects, irrespective of other risk factors. The higher incidence of hypertension was apparent predominantly in the older age groups.     

Beyond ONTARGET: angiotensin‐converting enzyme inhibition and angiotensin II receptor blockade in combination,a lesser evil in some?

Aim: Following the recent Ongoing Telmistartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) finding of adverse renal outcomes, dual renin‐angiotensin blockade has fallen out of favour, despite antihypertensive and antiproteinuric efficacy. However, in high‐risk severe hypertension, not studied in ONTARGET, whether combination treatment should be withheld or withdrawn is not clear. We examine the renal effects of angiotensin‐converting enzyme inhibitor (ACE‐I) and angiotensin II receptor blocker (ARB) monotherapy versus combination therapy in patients with type 2 diabetes and varying degrees of hypertension. Methods: Subjects attending a hospital diabetes centre were selected as case (combination therapy, n = 120) and control (monotherapy, n = 480). Subjects were matched for age, gender, ethnicity, estimated glomerular filtration rate (eGFR), blood pressure (BP) and study duration. Patients were stratified by BP, hypertension stage 1 (BP < 160/100, n = 506) and stage 2 (≥160/100, n = 94), and by treatment group. Data were analysed for the primary renal outcome of eGFR decline ≥20 ml/min, over a median of 3.7 years. Results: In keeping with the ONTARGET study, for stage 1 hypertension, combination treatment is significantly worse than monotherapy for the primary outcome of eGFR decline ≥20 ml/min (20 vs. 10.7%, p = 0.01). In contrast, for stage 2 hypertension, this endpoint was reached less often for combination versus monotherapy (12.0 vs. 23.2%, p = 0.2). Combination treatment was also not detrimental in patients with proteinuria or eGFR < 60 ml/min and was associated with fewer macrovascular events. Conclusion: Given that hypertension control is paramount and in the spirit of primum non nocere, these data are reassuring should clinicians choose to use ACE‐I and ARB combination therapy in the very hypertensive diabetic patient.     

Angiotensin converting enzyme inhibitors: Are they preferred first-line therapy?

In patients with hypertension, the primary goal is to reduce elevated blood pressure. All of the currently available and approved antihypertensive therapies are, by and large, equally efficacious. Some patient groups and individual patients may, however, respond differentially, and as a result one therapy may be more optimal than another. Overall, for uncomplicated hypertension and particularly for isolated systolic hypertension, diuretics should be considered for first-line therapy. However, comorbid conditions (which occur in > 50% of hypertensive patients) may prompt the need for a more ideal first-line therapy (eg, hypertension with diabetic nephropathy or with left ventricular dysfunction). Regardless, most patients with hypertension will require multidrug therapy to achieve the blood pressure goal, and an angiotensin converting enzyme (ACE) inhibitor may well be part of that therapy. Many going outcome trials comparing the newer therapies (such as ACE inhibitors) with diuretic-based therapy may redefine or clarify the use of different antihypertensive regimens.     

Are angiotensin converting enzyme inhibitors beneficial in patients with aortic stenosis?

Angiotensin converting enzyme (ACE) inhibitors may become an accepted form of treatment for aortic stenosis in the future.     

Are clinical endpoint benefits of angiotensin converting enzyme inhibitors independent of their blood pressure effects?

Both basic and experimental data indicate that the renin-angiotensin system through angiotensin II mediates its classic hemodynamic role, but also has a significant deleterious role in a number of cardiac, vascular, and renal disorders. Indeed, evidence indicates that angiotensin II negatively impacts endothelial function, cardiac remodeling, vessel wall hypertrophy, atherosclerosis, and progressive renal disease. Newer data point to a significant role for angiotensin II in inflammation and in inducing plasminogen activator inhibitor. This widespread negative effect can be countered by newer antihypertensive drugs, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers. Both small and large clinical trials suggest a large benefit of such drugs on not only organ-specific endpoints such as renal disease or proteinuria, but on global cardiovascular events. It does appear that when blood pressure is significantly elevated, lowering blood pressure does indeed provide protection for larger endpoints such as stroke. However, at lower blood pressure levels, a hemodynamically independent effect is likely to be contributing to the positive effects. We should embrace these effects and champion them for our patients.     

Emerging medical treatments for aortic stenosis: statins, angiotensin converting enzyme inhibitors, or both?

Aortic stenosis is the most common adult heart valve condition seen in the Western world and its incidence continues to rise. No established disease modifying treatments retard progression of the stenotic process. Recent insights into the pathogenesis of calcific aortic stenosis suggest that the disease mimics atherosclerosis. The natural history and progression of calcific aortic stenosis are described with particular emphasis on new and emerging medical treatments that may modify the disease process. In particular, statins and angiotensin converting enzyme inhibitors appear to hold promise but definitive evidence from large clinical trials is awaited.     

Are angiotensin converting enzyme inhibitors and angiotensin receptor blockers becoming the treatment of choice in African-Americans?

African-American patients constitute a significant and important group who are at high risk for developing hypertension-related complications. The proportion of African-American patients succumbing to or suffering from cardiovascular, renal, and neurologic sequelae is unacceptably high. Therefore, it is extremely crucial to develop appropriate therapeutic strategies for this vital subset of our society. The renin-angiotensin system may play a role in the pathophysiology of hypertension-related diseases, and therefore drugs that block this system, ie, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, may have a special indication for African-American patients. Although these drugs may not be the most efficacious agents in terms of blood pressure reduction, they have a major benefit in offering target organ protection and arresting disease progression in the African-Americans. Hence, contrary to the old notions, drugs blocking the renin-angiotension system have an important place in the management of hypertension and related disorders in African-American patients.     

Why are angiotensin converting enzyme inhibitors underutilised in the treatment of heart failure by general practitioners?

Treatment with angiotensin converting enzyme inhibitors confers significant morbidity and mortality benefits in patients with heart failure, yet previous studies have repeatedly shown that these drugs are underutilised in general practice. To investigate why this is the case, we conducted an anonymous questionnaire survey of 515 general practitioners in the Nottingham Health District. The response rate was 60.2%. We found that although 39.3% of respondents underestimated the poor prognosis associated with heart failure, 98% were aware of the prognostic benefits conferred by angiotensin converting enzyme inhibitors. However, 46.3% of respondents expressed concern about the potential adverse effects associated with angiotensin converting enzyme inhibitors, the main fears being hypotension and renal impairment. General practitioners who were concerned about adverse effects were significantly less likely to have initiated an angiotensin converting enzyme inhibitor for heart failure than those who were not (P<0.01). Further research is needed to identify which patients can safely be commenced on angiotensin converting enzyme inhibitors in general practice. In the meantime, general practitioners should be encouraged to refer patients whenever they are concerned about initiating angiotensin converting enzyme inhibitors in the community.     

Do angiotensin II receptor antagonists substitute angiotensin converting enzyme inhibitors in the treatment of high blood pressure?

Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (AIIA) are both pharmacological groups that inhibit the actions of angiotensin II. ACEI prevent the formation of angiotensin II from angiotensin I, whereas A II A inhibit the final crucial step of angiotensin II binding with the AT1 receptor site. A similar antihypertensive efficacy has been described for both groups but A II A drugs have a better safety profile above all due to the absence of dry cough. Despite the fact that evidence with ACEI is more conclusive, A II A seems to achieve the same protective effects on the target organ damage in hypertensive patients. At present, ACEI are the drugs of choice in the treatment of patients with cardiac dysfunction and failure. The information of ongoing trials with A II A will be of great value in deciding the optimal treatment for hypertensive patients with different cardiovascular diseases.     

Debates on the concomitant use of aspirin and Angiotensin converting enzyme inhibitors: will the consensus be reached?

During last 10 years the potential interaction between aspirin and angiotensin converting enzyme inhibitors (ACEI) has received considerable attention. Retrospective analysis of randomized trials and their meta-analyses gave conflicting results concerning existence and effects of this interaction. Taking into consideration proven benefit of both aspirin and ACEI, restricting their combined use is premature. Further studies of this issue are warranted.     

Are all angiotensin-converting enzyme inhibitors interchangeable?

In the treatment of most medical conditions, there are many choices. A critical question for practicing clinicians is: "Are all drugs within a class interchangeable?" In the past decade, the market has seen a proliferation of drugs within popular drug classes. The original drugs within a class typically have better scientific documentation than the newer ones, which are often referred to as "me-too" drugs. Due to a lesser financial investment, the latter may be available at a lower cost. Good reasons exist for grouping drugs, however, there is no accepted definition of the term "class effect." Although members of a drug class share main actions, they may have clinically important differences in terms of efficacy and safety. There are many such examples in the literature. This article reviews the class effect concept as it applies to the angiotensin-converting enzyme (ACE) inhibitors. Only half of the 10 ACE inhibitors available in the U.S. have been shown to improve survival and reduce morbidity in patients with heart failure or myocardial infarction. It is unknown whether the other five have the same safety and efficacy profiles or what their optimal doses are. Thus, we do not know whether all ACE inhibitors are fully interchangeable. The practice of medicine ought to be based on solid scientific evidence, not on assumptions or extrapolations. For our patients, such practice is a legitimate expectation. Therefore, it seems prudent to recommend that patients requiring ACE inhibitor therapy be prescribed one that has been proven effective and safe.     

Optimal strategies for preventing progression of renal disease: Should angiotensin converting enzyme inhibitors and angiotensin receptor blockers be used together?

Interruption of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT₁ receptor blockers has been shown to delay progression in a variety of renal diseases, suggesting that the RAS, and its major effector molecule, angiotensin II, are important players in renal pathophysiology. Both antagonists combine inhibition of deleterious effects of angiotensin II with activation of potentially beneficial pathways mediated by nitric oxide and prostaglandins. Some concerns have been raised about the completeness of the RAS blockade achieved by these agents. ACE-independent pathways can generate angiotensin II, whereas increases in angiotensin II levels may compete with the AT₁ receptor blocker at the receptor site. It has been suggested that an ACE inhibitor/AT₁ receptor blocker combination offers a better therapeutic effect than treatment with either agent alone. In this review, we focus on mechanisms of actions of ACE inhibitors and AT₁ receptor blockers, implicate them in the rationale for the use of an ACE inhibitor/AT₁ receptor blocker combination, and discuss evidence evaluating the renal effects of the combination as compared to the effects of a single agent. There is a surprising lack of information about the nephroprotective potential of the combination, allowing no consistent conclusions about the superiority of the combination over the single agent. Several experimental and clinical reports suggest that in some conditions, the combination may be beneficial. Rather than providing unequivocal evidence for the use of combination treatment in the renal disease, these studies should be considered as stimuli for more detailed exploration of this issue.