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Prevention of aortic valve disease: between doubts and certainties

Aortic valve disease and its prevention is a topic in constant evolution. Currently, medical therapy able to prevent the development of aortic valve disease is not available. For aortic stenosis, the main family of drugs to have been evaluated is statins but randomised trials have consistently shown that they do not affect the progression of the disease. Cardiovascular risk factors could increase the risk of stenosis and could be an avenue to prevention. Long-term exposure to higher blood pressure should be considered a risk factor for both aortic stenosis and aortic regurgitation. Prevention also includes avoidance of rheumatic fever and endocarditis.

Valvular Heart Disease


Introduction

Prevention of aortic valve disease is a topic of current research. Interest in this topic has been fuelled by the significant mortality and morbidity associated with valvular heart diseases, added to the risk of interventions [1,2]. Aortic stenosis is the most common valvulopathy in adults [3]. Possible prevention strategies have been analysed in the literature. Several theories have been investigated regarding how to avoid the progress and severity of the disease, and thus deduce a strategy for prevention. The modifiable causes of aortic valve stenosis and regurgitation are not well understood. Medical therapy, cardiovascular risk factors and prevention of pathologies, such as rheumatic fever and endocarditis, are the most interesting fields which have been investigated in terms of prevention.

The usefulness of medical therapy

Aortic stenosis has been evaluated pharmacologically with a view to prevention and in order to reduce the progression of its severity.

Calcific aortic valve disease, the most common aetiology, is defined as a multifactorial, active process characterised by fibrosis, extracellular matrix degradation, cellular inflammation, lipid accumulation, neo-angiogenesis and calcium nodule formation [4]. The complex and multifactorial presence in pathogenetic mechanisms has determined the possibility of studying the different targets which influence disease progression. Greatest attention has been directed towards lipid-lowering therapies. Interest in these therapies arises from the theory that the cellular mechanisms involved in the disease progression resemble atherosclerosis [5]. In this regard, lipid-lowering therapies can prevent stenosis progression and therefore reduce the need for aortic valve replacement.

After several decades of studies with conflicting data, randomised trials have established that statins do not affect the progression of aortic stenosis. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial was a randomised, double-blind trial conducted by Rossebø et al involving 1,873 patients with mild to moderate aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. The results documented an average reduction in low-density lipoprotein cholesterol (LDL-C) of at least 50%, compared to placebo, with the combination of simvastatin and ezetimibe.

Despite these consistent data, there was a lack of any effect on the progression of aortic stenosis [6]. In addition, two other trials, Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) [7], and Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin (ASTRONOMER) [8], studied the role of the statins; however, neither showed any effect in reducing the rate of progression.

Currently, there are no data to indicate the use of statins. European recommendations do not suggest lipid-lowering therapy for prevention of aortic stenosis progression [1]. Despite the latter recommendation, the use of statins is currently indicated as medical therapy to prevent atherosclerosis. In the development of aortic stenosis, atherosclerosis is an important risk factor and statins are recommended to prevent it.

Finally, another candidate for reducing the progression of aortic stenosis is renin-angiotensin-aldosterone system (RAAS) blocking therapy. The use in disease prevention arises from the presence, in the aortic valve, of angiotensin-converting enzymes (ACE) and angiotensin II receptors. Angiotensin II attracts inflammatory cells and promotes fibrosis [9]. Despite observational cohort studies associating RAAS blocking therapy with reduced aortic stenosis progression, this currently cannot be recommended in the absence of prospective randomised trials [10].

The role of cardiovascular risk factors

Cardiovascular risk factors can increase the risk of aortic valve disease. Previous studies have been conducted to define better the link between specific risk factors and aortic stenosis and regurgitation. The target is to find a direct association to lead future efforts in preventing and reducing progression.

Aortic stenosis has been associated with risk factors such as arterial hypertension, hypercholesterolaemia, diabetes mellitus, metabolic syndrome and smoking. In a cross-sectional study by Stewart et al of 5,201 subjects ≥65 years of age enrolled in the Cardiovascular Health Study, risk factors such as age, male gender, smoking, history of hypertension, LDL-C and lipoprotein(a) were independently associated with aortic stenosis and aortic sclerosis [11].

In the Multi-Ethnic Study of Atherosclerosis (MESA) in 6,780 participants with metabolic syndrome (n=1,550), diabetes mellitus (n=1,016), or neither condition, the prevalence of aortic valve calcium was compared by evaluation with computed tomography. The results documented the association of diabetes mellitus and metabolic syndrome with increased risk of aortic valve calcium [12]. Smith et al evaluated whether genetic data were consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease. Using a Mendelian randomisation study design, they found that genetic predisposition to elevated LDL-C was associated with the presence of aortic valve calcium and incidence of aortic stenosis.  Furthermore, they suggested that earlier intervention to reduce LDL-C might be useful to prevent aortic valve disease [13].

However, in other studies, some risk factors were found to have a negative association with prevention and the progression rate of aortic stenosis. As discussed above, three randomised trials (SALTIRE, SEAS and ASTRONOMER) did not show that reduction in LDL-C slowed the progression and reduced the risk for aortic valve replacement.

Discordance and doubts in the literature about the association with specific risk factors are related to the types of study conducted. Most studies were cross-sectional, retrospective and characterised by selected populations. On the other hand, there have been few prospective, observational or large, representative, population-wide studies. Ljungberg et al conducted a prospective, observational study of traditional cardiovascular risk factors and their association with valvular heart disease. They found that classic cardiovascular risk factors predicted surgery for aortic stenosis, but none was predictive of valvular heart disease after exclusion of patients with coronary artery disease.

Indeed, a strong association between hypertension, high cholesterol levels, diagnosis of diabetes mellitus, active smoking and aortic stenosis was only found with concomitant coronary artery disease [14]. The CANHEART Aortic Stenosis Study was an observational cohort study which followed 1.12 million individuals (age 65 and older) for a median of 13 years. In the study, severe aortic stenosis developed in 20,995 subjects. Smoking status was not recorded in the databases and body mass index and waist circumference were not available in the data set. Cardiac risk factors such as hypertension, diabetes and dyslipidaemia had independent and dose-response associations with incident aortic stenosis. The population-attributable risk associated with three cardiac risk factors was 34.4% and all three risk factors involved one third of the incidence of severe aortic stenosis [15].

On account of discordance between the various results and the limited literature, further longitudinal data from large, representative, population-wide and prospective, observational studies are needed to clarify the correct role of risk factors.

Aortic regurgitation has several risk factors, such as bicuspid aortic valve, diseases of the ascending aorta and other valvular malformations, but does not have prospective targeted studies assessing the association between cardiovascular risk factors and the risk of developing valve regurgitation.

An interesting study was conducted by Rahimi et al assessing the association between high blood pressure and the risk of aortic valve disease. The observational longitudinal study confirmed the consistent role of arterial pressure as a risk factor for aortic valve regurgitation or stenosis.

The relationship was investigated in 5.4 million patients with no known cardiovascular disease or aortic valve disease at baseline. Aortic stenosis was diagnosed in 20,680 patients (0.38%) and aortic regurgitation in 6,440 (0.12%) during a median follow-up of 9.2 years. The mean age at the diagnosis of aortic stenosis was 64.2 (12.1) years and 57.0 (16.5) years for aortic regurgitation. At baseline, patient characteristics included one third smokers and 1.1% diabetics. Furthermore, a 40% higher risk of aortic stenosis or aortic regurgitation was associated with a 20 mmHg higher systolic blood pressure, with stronger associations in younger groups.

In conclusion, they found an increased risk of aortic stenosis and regurgitation in association with higher blood pressure and pulse pressure. The conclusions suggest that prevention of aortic valve disease may be possible in clinical practice in the treatment of arterial hypertension; however, further research is needed to assess the causal association observed in the study [16].

Prevention of rheumatic fever and endocarditis

Medical therapy and identification and treatment of cardiovascular risk factors remain much-debated topics in terms of the prevention of aortic valve disease. However, a consolidated option, as recommended by the European Guidelines for the management of valvular heart disease, is the prophylaxis of endocarditis and rheumatic fever [1]. Preventing aortic valve stenosis or regurgitation is also a way of avoiding rheumatic heart disease and endocarditis with complications.

Rheumatic fever

Rheumatic fever occurs as a result of group A streptococcal pharyngitis. The acute phase is characterised by mitral and aortic regurgitation and may progress, in half of all patients, to chronic rheumatic heart disease. The typical features are fibrotic leaflets with thickening, calcification and retraction. Patients with rheumatic valve disease may present regurgitant or stenotic disease. In case of aortic stenosis, the commissural fusion results in progressive disease. The characteristic alterations of the rheumatic disease generally induce a central aortic regurgitation. Finally, post-rheumatic aortic regurgitation is more frequent than aortic stenosis.

Prevention of rheumatic heart disease means the prevention of the first attack of acute rheumatic fever. The objective of primary prevention is the proper identification and adequate antibiotic treatment of group A beta-haemolytic streptococcal tonsillopharyngitis. The key is the appropriate antibiotic treatment to prevent the acute rheumatic fever, although non-preventable cases are documented in cases of inapparent infections or patients not seeking medical attention.

The treatment of choice in primary prevention is penicillin (either oral penicillin V or injectable benzathine penicillin) whereas, in case of penicillin-allergic individuals, the alternatives include a narrow-spectrum oral cephalosporin, oral clindamycin, or various oral macrolides or azalides [17,18].

Endocarditis

Infective endocarditis is characterised by vegetations and destructive lesions. Aortic regurgitation is related to vegetations, leaflet perforation or perivalvular abscess communicating with the left ventricle and aorta. Among the cases of aortic regurgitation, endocarditis accounts for 10%. Valve obstruction is less frequent and determined only by large and mobile vegetation.

Endocarditis prophylaxis is based on antibiotic treatment, in specific patients, when a high-risk procedure is performed. Prophylaxis should only be considered for dental procedures involving manipulation of the gingival or periapical region of the teeth or manipulation of the oral mucosa. Patients at highest risk for infective endocarditis who should be considered are patients with any prosthetic valve, patients with a previous episode of infective endocarditis and patients with congenital heart disease. Patients at intermediate risk are not recommended for antibiotic prophylaxis. All other forms of native valvular disease, including bicuspid aortic valve, mitral valve prolapse and calcific aortic stenosis, are part of the intermediate risk [19].

Dental hygiene

A risk factor which can reveal endocarditis is poor dental hygiene. Indeed, the entry route for bacteria into our body can be the inflamed and ulcerated gingival area around a tooth. Good dental hygiene is associated with a reduced risk of developing endocarditis due to reduced bacteraemia. The occurrence of bacteraemia is also reported after tooth extraction. Daily care is needed to reduce the risk of developing periodontitis and eliminate gingivitis and the need to extract teeth. Strict dental hygiene should be followed by the general population and particularly reinforced in patients in countries with a high incidence of endocarditis, such as in Africa and parts of Asia.

Prevention measures are based on good daily dental hygiene, using optimal quality toothbrushes, and dental follow-up. European recommendations underline the importance of dental hygiene, which should always be advised in intermediate- and high-risk patients. Dental follow-up in high-risk patients should be performed twice a year and in intermediate-risk patients yearly [20].

Conclusion

Prevention of aortic valve disease still requires research studies to define the correct approach. Currently, although medical therapy to prevent disease and progression has not been recommended, the use of statins, as a medical therapy for preventing atherosclerosis, a risk factor in developing stenosis, is recommended. Risk factors, first of all arterial hypertension, could be associated with the risk of aortic stenosis and regurgitation; treatment could be beneficial for prevention. Prophylaxis for rheumatic fever and endocarditis must be performed according to the current indication to avoid the risk of consequent valvular diseases.

References


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Notes to editor


Author:

Francesco Perone, MD

Department of Angio-Cardio-Neurology and Translational Medicine, IRCCS Neuromed, affiliated to “Sapienza” University of Rome, Pozzilli, Italy 

 

Address for correspondence:

Dr Francesco Perone, Via Unità Italiana, N. 53, 81100 Caserta, Italy

E-mail

 

Author disclosures:

The author has no conflicts of interest to declare.

 

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.