An Update on Aortic Stenosis: Pathophysiology, Progression, Diagnosis and Current treatment options

Aortic stenosis (AS) is the second most common valvular abnormality. Incidence increases with age and it is present in up to 2% of 60 year olds and 10% of 80 year olds. The disease process comprises fibrocalcification of the valve that results in orifice narrowing and LV outflow obstruction and is referred to as calcific aortic valve disease (CAVD). Aortic valve stenosis causes increased LV pressure, compensatory LV hypertrophy and affects cardiac output. Symptoms comprise a “classic triad” of shortness of beath, chest pain or syncope. Previously AS was considered a “degenerative process” that could not be modified however recent histological assessment confirms that AS is an active process of oxidised lipids and infiltrating inflammatory cells, perhaps opening pathways to future preventative therapies.

Untreated symptomatic AS has a two-year mortality of up to 50%. To date no pharmacological treatment has been shown to slow disease progression. Therefore, treatment options for severe AS are limited to valve replacement either surgically or percutaneously with a transcatheter system.

Although effective treatments, they do expose the patient to peri-procedural risk, possible need for anticoagulation (metallic valves) or risk related to bioprosthetic valve degeneration.

Aortic stenosis was previously considered a degenerative valve process; however in-vitro studies indicate that this view may be oversimplistic. It is now thought that there is an initiation phase followed by a propagation phase as valve disease progresses from aortic sclerosis, through mild, moderate and severe AS. This involves a complex network of cellular and molecular mechanisms. The initiation phase appears to start with endothelial damage as a result of mechanical forces and shear stress across the valve.

This facilitates lipid infiltration and propagates an inflammatory response. The process then progresses to the propagation phase. During this phase valve interstitial cells (VICs), a fibroblastlike cell of the spongiosa layer, convert to osteoblast-like cells and secrete calcium.

Levels of macrocalcification of CAVD vary by gender.

Females have a lower burden of calcification that is reflected in a lower Agatson scores on CT imaging (1200 for females with severe AS versus 2000 for males). Conversely, post-operative stenosed aortic valves explanted from females have higher levels of fibrosis. Diseased aortic valves also have evidence of angiotensin converting enzyme (ACE) colocalising with apolipoprotein B in the extracellular matrix, and myofibroblasts in the fibrosa have shown evidence of Angiotensin Type-1 (AT-1) receptors, possibly implicating the RAAS system in disease propagation.

Risk factors for AS mirror those for coronary atherosclerosis. These include age, being male, hypertension, CKD, hypercholesterolaemia, smoking, diabetes mellitus and established vascular disease. Valvular specific risk factors include congenitally abnormal leaflets e.g. bicuspid valve (BAV), or previous rheumatic heart disease. Shear stress is particularly relevant when leaflets are abnormal. Patients with BAVs typically develop severe AS one to two decades earlier than those with tricuspid aortic valves.

Patients may also have genetic predisposition to BAV and general AS. A Swedish registry study identified NOTCH1 mutations as a risk factor for BAV.

Aortic stenosis is usually diagnosed clinically through detection of an ejection systolic murmur. This is heard loudest in the right sided second intercostal space, radiates to the carotid arteries and is confirmed by transthoracic echocardiogram (TTE). Typical echo findings of severe aortic stenosis include restricted movement of calcified leaflets, a transvalvular velocity > 4m/s, mean pressure gradient of > 40mmHg, an aortic valve area < 1cm2 and a dimensionless index of <25. Related parameters for assessing severity and treatment include LV ejection fraction (LVEF), degree of aortic regurgitation (AR), assessment of other valvular abnormalities and measurement of right heart pressures.

Low flow low gradient AS occurs when valve gradients are disproportionate to valve area. In these cases severity may be more accurately determined by exercise or dobutamine stress echocardiography (DSE). This helps to distinguish severe versus pseudo-severe AS. Aortic valve area does not increase in true severe AS with increased cardiac output (CO). Transoesophageal echocardiogram or Cardiac CT (CCT) can also help to elucidate severity in uncertain cases. A calcium score of >2,000 for men and >1,200 for women on CCT indicates a high likelihood of severe AS.

Aortic sclerosis is the term used for early abnormalities of the aortic valve. These comprise valve thickening and calcification that occurs without outflow tract obstruction or elevation of transvalvular velocity gradient on TTE (<2m/s). Clinically patients may have an ejection systolic murmur on examination, without an effect on the second heart sound.

Aortic sclerosis (AScl) is common, being present in up to 25% of 65-74 year olds and up to 48% of 84 year olds, and is a recognised antecedent of AS. Determinants of progression to AS remain unclear. Studies indicate that only 9% progress to any degree of AS over 5 years.

Aortic sclerosis is a marker of increased cardiovascular risk. Studies show an increased risk of death, MI, ventricular arrhythmia and ventricular systolic dysfunction among patients with aortic sclerosis versus those without. Thus patients with aortic sclerosis may be candidates for more aggressive risk factor management and more systematic follow up.

Tradition cardiac risk factors only predict the presence of AS/AScl, not rate of disease progression. Once valvular damage is sufficient to cause an outflow gradient on TTE, valvular dysfunction progresses roughly at a rate of 0.1-0.3m/sec increase in maximum gradient per year. This translates to approximately 3-10mmHg increase in mean gradient, and drop in aortic valve area of 0.1cm2 per year. There is significant interpatient variability however, and in some patients aortic stenosis may progress more rapidly such as those with renal impairment.

As AS increases so does left ventricular (LV) afterload and adaptive change in the left ventricle, so called LV remodelling, ensues. LV size, wall thickness, structure and function evolve.

LV wall stress reflects afterload on the LV and results in direct tension on individual myocardial fibres. It is modulated by LV pressure, wall thickness and diameter (law of LaPlace). Increased wall stress leads to myocyte hypertrophy which can occur in a concentric or eccentric pattern. Progressive LVH is a compensatory mechanism that initially improves wall stress and maintains CO until severity of AS precludes further increases of CO and LV changes become maladaptive. Patterns of LVH may differ by gender.

As LVH progresses myocardial oxygen demand increases and coronary perfusion deficits arise. Myocardial hypo perfusion causes subendocardial ischaemia, necrosis and fibrosis and reduced diastolic filling time. Fibrosis causes myocardial stiffness, elevated LV end diastolic pressures and impaired diastolic function. This perpetuates a cycle of ischaemia and fibrosis and leads to further decline in LV function. Left ventricular ejection fraction (LVEF) may be maintained at this time, but LV global longitudinal strain (GLS) is affected early in the disease process and correlates with mortality/survival post AVR.

LV wall stress activates neuroendocrine, paracrine and autocrine systems to maintain CO. These include the RAAS, sympathetic nervous system, oxidative pathways and proinflammatory cytokines (TGF-beta1/TNF).

To date no medication has been shown to slow AS progression. If was postulated that statins would dampen valvular inflammation and thus retard AS progression, but clinical trials have failed to show benefit. PCSK9 inhibitors are currently undergoing similar trials. Studies of ACE inhibitors (LIFE trial), losartan and atenolol have also failed to show benefit.

Untreated symptomatic severe AS is associated with a two- year mortality of up to 50%, however timing of intervention remains contentious. Previous guidelines recommended active surveillance for patients with asymptomatic severe AS, though it is recognised that symptoms can be subjective and may be masked by co-morbidities such as chronic obstructive pulmonary disease (COPD). This makes safe timing for treatment of such patients challenging.

On-going studies attempt to identify asymptomatic AS patients at higher risk for whom surveillance may not be appropriate. Some high-risk parameters have already been incorporated into treatment guidelines. These include depressed LVEF, very high gradient AS (> 5m/s), rapidly increasing gradient (> 0.3m/s per year), abnormal blood pressure response to exercise stress testing, or unexplained elevation of brain natriuretic peptide levels (BNP). Others that remain subject of trials include degree of LVH, left atrial size, LV strain patterns on TTE, autonomic parameters and abnormal biomarker levels such as troponin, fetuin-A, and copeptin.

Current treatment of severe AS focuses on valve replacement, either surgically with a bioprosthetic or metallic valve (SAVR), or minimally invasively with a transcatheter bioprosthetic aortic valve (TAVR) using either a balloonexpandable or self-expandable valve system.

Surgical risk previously precluded treatment of a significant cohort of patients with severe AS. This unmet need prompted development of TAVR platforms in the early 2000s. Surgical risks are usually calculated with risk models such as the STS-PROM (Society of Thoracic Surgeons predicted risk of mortality) score or EuroScore and classify patients as low, intermediate or high risk for mortality and post-operative complications (arrhythmia, stroke, bleeding, poor wound healing, thrombosis risk and infection). Average length of stay after an uncomplicated SAVR is 7 days in hospital.

TAVR was initially offered to patients at high surgical risk, but recent trials have shown that TAVR is non-inferior to SAVR in patients without a bicuspid valve at low and intermediate surgical risk (PARTNER 3 trial, Evolut low risk trial). Current TAVR related risks include stroke (approx. 1%), femoral access site bleeding, arrhythmia, pacemaker implant (approx. 6%), increased risk of significant aortic regurgitation versus SAVR and death (approx. 1%). Average in hospital length of stay after an uncomplicated TAVR is 2 days.

Thus, the ESC guidelines currently recommend TAVR for patients >75 years of age and those with high surgical risk (STS-PROM/ EuroSCORE II > 8%), SAVR for patients <75 years, those at low surgical risk (STS-PROM/ EuroSCORE II <4%) and those with unfavourable anatomy for TAVR, and either option can be considered for patients with intermediate risk depending on anatomical suitability and patient preference.

Severe aortic stenosis is a common abnormality that is associated with significant mortality and prevalence increases with age. Current treatment options include surgical and transcatheter aortic valve replacement. There is growing evidence for the safety and efficacy of TAVR among a broad patient cohort.