Almanac 2014: Aortic Valve Disease

The new 2014 American Heart Association/American College of Cardiology valve guidelines remain congruent with the basic principles put forth in the 2012 European Society of Cardiology document and go on to introduce several new concepts. (1, 2) These guidelines emphasise the importance of centres of excellence in valvular heart disease with multidisciplinary Heart Valve Clinics (3) to integrate the clinical, imaging, interventional and surgical expertise needed for optimal care of these patients. In addition, the concept of valve disease stages now is central to diagnosis and management. Each valve stage is defined by patient symptoms, valve anatomy, valve haemodynamics and LV changes. The four stages are:

• Stage A: At risk for valve disease, for example, patients with aortic sclerosis or a bicuspid aortic valve.
• Stage B: Progressive valve disease, equivalent to mild-to-moderate aortic stenosis (AS).
• Stage C: Severe asymptomatic valve disease, defined by valve anatomy and haemodynamics, with subdivisions for normal or abnormal LV function.
• Stage D: Severe symptomatic AS, including subsets for low-gradient low-flow severe AS with a low or normal LVEF.

Other important changes in these guidelines are (1) an integrated approach to risk assessment before surgery or transcatheter interventions and (2) consideration of earlier intervention in adults with asymptomatic very severe AS, defined as an aortic velocity of 5 m/s or higher. (4)

BICUSPID AORTIC VALVE DISEASE

A congenitally bicuspid aortic valve is present in about 1% of the population with nearly all of these patients eventually requiring valve surgery either for aortic regurgitation as young adults or for AS later in life. Most patients with a bicuspid aortic valve also have aortic sinus and ascending aortic dimensions larger than the normal population. In addition, a subset of bicuspid aortic valve patients is at risk of progressive aortic dilation and has an increased risk of aortic dissection. However, we do not know how to identify which patients are at risk for progressive aortic disease and thus require more frequent imaging. In a case control study of 43 patients, matched for age and gender, bicuspid valve patients had evidence for endothelial dysfunction and inflammatory biomarkers with the severity of these abnormalities correlating with valve dysfunction but not with progressive aortic dilation. (5) A retrospective multicentre study confirmed that aortic dilation was present in 87% of bicuspid valve patients (n=353), with sinus dilation more typical with right–left coronary cusp fusion but ascending dilation independent of valve morphology (Figure 1). The rate of aortic dilation was not related to baseline aortic diameter or valve morphology and 43% of bicuspid valve patients had no significant change in aortic size over a mean follow-up of 3.6±1.2 years. (6)

Figure 1. (A) Basic morphologies of bicuspid aortic valve (BAV). Panel A shows a typical BAV in diastole with a small raphe (arrow) between the right (R) and left (L) coronary cusps. In systole (panel B), commissures are located at 10 and 4 o-clock (arrows). Panel C depicts an atypical BAV in diastole with a prominent raphe (arrow) between the right (R) and non-coronary (N) cusps. In systole (panel D), commissures are located at 1 and 7 o’clock (arrows). (B) Aortic dilatation phenotypes. Panel A depicts a patient with Marfan syndrome and predominant dilatation of the sinuses of Valsalva. Panel B depicts a patient with BAV and predominant dilatation of the tubular ascending aorta. LA, left atrium; Ao, ascending aorta. (6)

In a single centre cohort of patients who present with an aortic dissection, those with a bicuspid valve (47 patients compared with 53 with a trileaflet valve) were almost a decade younger and more often had a history of aortic dilation (49% vs 17%, p=0.001) or previous aortic valve replacement (AVR; 23% vs 6%, p=0.02). (7) Aortic diameter was larger in bicuspid valve patients (66±15 vs 56±11 mm, p=0.0004) but the clinical presentation was otherwise similar. Taken together, these studies underline the need for careful evaluation of the aorta and appropriate periodic evaluation in adults with a bicuspid aortic valve, as well as the importance of educating patients about symptoms of aortic dissection. In addition, screening first degree relatives of patients with a bicuspid valve and dilated aorta should be considered because some families have an inherited form of this condition.

CALCIFIC AORTIC VALVE DISEASE

Prevalence

The prevalence of calcific aortic valve disease increases with age. Mild changes, termed aortic sclerosis (Stage A disease) are present in about 25% of all adults over 65 years of age and are a marker for adverse cardiovascular events with about a 50% increased risk of mortality over 5 years even in the absence of valve obstruction. (8) These findings were confirmed in a study of 3944 subjects in the Heinz Nixdorf study. Aortic valve calcification scores in the third tertile were associated with a higher incidence of coronary (HR 2.11, 95% CI 1.28 to 3.81) and cardiovascular events (HR 1.67, 95% CI 1.08 to 2.58), even after adjustment for Framingham risk factors. (9) Although valve calcification did not provide additive predictive value over coronary calcium scores in this study, in clinical practice echocardiographical imaging avoids ionising radiation and is more widely available than CT imaging. Thus, it remains unclear if aortic sclerosis on echocardiography should be additive to risk models for cardiovascular risk.

In the Tromsř population-based study of 3273 participants, more severe calcific disease was present in 164 subjects with a marked increase in prevalence of significant valve obstruction with age (Figure 2). In adults over 50 years of age, the annual incidence rate of AS was 4.9% with an average annual increase in aortic transvalvular gradient of 3.2 mm Hg. (10) In these patients, who were treated with valve replacement as needed for severe symptomatic disease, outcomes were similar for patients with AS and the general population.

Figure 2. Prevalence of aortic stenosis. The figure shows weighted mean values in the combined survey of Tromsř 4, 5 and 6, with hospital data included. The surgery group is included in the main group. (10)

Genetics

Although the phenotype of calcific aortic valve disease typically presents late in life, there is increasing evidence that there is an underlying genetic predisposition to this condition. In a genome-wide association study of 6942 participants, a single nucleotide polymorphism (SNP) in the locus for lipoprotein(a) (Lp(a)) was associated with the presence of aortic valve calcification as assessed by CT scanning. (11) In addition, genetically determined serum Lp(a) was associated with both incident AS and with AVR. (11) In a separate study using a Mendelian randomisation study design, plasma low-density lipoprotein cholesterol was associated with an increased risk of incident AS (HR per mmol/L, 1.51; 95% CI 1.07 to 2.14; p=0.02). (12) An SNP-based risk score for predisposition to elevated plasma lipids was also associated with aortic valve calcium and AS. (12) Taken together, these studies are strong evidence that an underlying genetic predisposition to elevated serum lipid levels is associated with the development of calcific valve disease. In the future, this might allow therapy to be targeted towards patients at highest risk of developing valve disease.

Measure of AS severity

Echocardiographical and haemodynamical measures of AS severity have generated considerable confusion, in large part related to the naive notion that velocity, gradient and valve area should always match and fall into clear categories of mild, moderate or severe. Ideally, a simple single measure would allow accurate diagnosis of AS severe enough to require valve replacement. Unfortunately, it is not that easy. In clinical practice, evaluation should include measurement of aortic velocity, mean transaortic gradient and calculation of valve area by the continuity equation. Although adjusting valve area for body size makes sense conceptually, indexing aortic valve area (AVA) for body size significantly increased the prevalence of apparently severe AS by including larger patients with only mild-to-moderate disease. (13) In addition, indexing AVA did not improve the predictive accuracy for clinical events in patients with mild-to-moderate AS. (14) In an editorial, Professors Pibarot and Dumesnil suggest a practical approach to resolving apparent discrepancies between valve area and mean gradient as shown in Figure 3. (15)

Figure 3. Proposed algorithm for differential diagnosis in patients with aortic stenosis and preserved LVEF presenting with a small AVA (<1.0 cm2) but a low mean gradient (<40 mm Hg). AS, aortic stenosis; AVA, aortic valve area; AVAi, indexed aortic valve area; ∆Pmean, mean transvalvular gradient; BNP, B-type natriuretic peptide; CT, multislice CT; LVEDD, LV end-diastolic diameter; LVEDVi, indexed LV end-diastolic volume; RWTR, relative wall thickness ratio; SVi, stroke volume index; Zva, valvuloarterial impedance. (15)

Another measure of AS severity that accounts for body size is the ratio of the velocity proximal to and in the stenotic valve the velocity ratio with normal being close to 1.0 and with smaller numbers indicating more severe valve disease. For example, a velocity ratio of 0.25 indicates a valve area 25% of normal for that individual. The velocity ratio is most useful to help distinguish low-flow severe AS from moderate AS in patients with a small valve area but only a moderately increased velocity or gradient. In 435 patients in the Simvastatin and Ezetimibe in Aortic Stenosis study with an AVA<1.0 cm2, mean gradient ≤40 mm Hg and LVEF≥55%, aortic valve events occurred more often in patients with a velocity ratio <0.25 compared with those with a higher velocity ratio (57% vs 41%; p<0.001) but did not provide additive value to mean gradient for prediction of clinical events (Figure 4). (16)

Figure 4. Kaplan–Meier curves demonstrating significantly more aortic valve events over 42±14 months in patients with a velocity ratio <0.25 (blue line) versus patients with a velocity ratio ≥0.25 (p<0.001 with log-rank test, (A) and a trend towards an increased rate of cardiovascular death (B). There was no statistically significant difference with respect to ischaemic events (C) or all-cause mortality (D). (13, 16)

Low-output low-gradient AS

Increased recognition of symptomatic AS in patients with only a moderate increase in transvalvular velocity or mean gradient has led to further studies on low-output low-gradient severe AS and the realisation that this condition can occur even with a normal LVEF. The new valve guidelines4 provide clarity to this discussion with new definitions of severe AS:

• Stage D1 or high-gradient severe symptomatic AS. Key parameters are a calcified or thickened aortic valve with reduced mobility and an aortic velocity over 4 m/s. AVA is typically 1.0 cm2 or less but this number is not required for diagnosis.
• Stage D2 or low-gradient severe symptomatic AS with a low LVEF. Key measures are a calcified immobile valve with a resting AVA ≤1.0 cm2, aortic velocity 2.
• Stage D3 or low-gradient severe symptomatic AS with a normal LVEF. Diagnosis is based on a calcified immobile valve with an AVA ≤1.0 cm2, aortic velocity 2/m2 and an indexed stroke volume 2 measured with the patient is normotensive.

Symptoms in AS

When symptom status is unclear in adults with AS, previous studies have suggested that measurement of serum B-natriuretic peptide (BNP) levels provides additional prognostic value. However, in a single centre study of 361 patients older than 70 years with at least mild AS, Nt-proBNP levels correlated only modestly with outcome on univariate analysis, but not on multivariate analysis when adjusted for age, sex and AS severity suggesting this parameter be used with caution in elderly patients with AS. (17)

TRANSCATHETER AORTIC VALVE IMPLANTATION

Transcatheter aortic valve implantation (TAVI) is widely accepted as the most appropriate approach for patients with symptomatic severe AS who have a prohibitive risk for surgical intervention. (18) The randomised clinical trial of a transcatheter self-expanding aortic valve bioprosthesis in 795 patients at 45 centres in the USA confirmed the benefit of this procedure in patients at high risk for surgical intervention. (19) All-cause mortality at 1 year was lower with TAVI compared with surgical AVR (14.2% vs 19.1%). (19) The choice of balloon-expandable versus self-expanding TAVI depends to some extent on patient characteristics, but a small, randomised study suggests that a successful procedure is more likely with a balloon-expandable valve. (20)

Risk stratification

Evaluation of risk in patients being considered for surgical or transcatheter valve replacement has largely been based on surgical risk scores, which may be not fully applicable to transcatheter procedures. The 2014 Valve Guidelines recommend that, in addition to surgical risk scores, factors such as frailty, other organ system involvement and procedural specific factors also be considered. A simple risk score for prediction of early mortality after TAVI has been proposed by the FRANCE-2 Investigators based on predictors of 30-day mortality in 3833 consecutive patients undergoing balloon-expandable (67%) or self-expanding (33%) TAVI (Figure 5). (21, 22)

Figure 5. FRANCE-2 risk score or prediction of early mortality after transcatheter aortic valve implantation. (21) The relationship between the score value and predicted early mortality after transcatheter aortic valve implantation is shown. *The definition of critical state corresponds to the definition of the Euroscore as follows: any one or more of the following: ventricular tachycardia or fibrillation or aborted sudden death, preoperative cardiac massage, preoperative ventilation before arrival in the anaesthetic room, preoperative inotropic support, intra-aortic balloon counterpulsation or preoperative acute renal failure (anuria or oliguria <10 mL/h). (21) BMI, body mass index; NYHA, New York Heart Association; PAP, pulmonary artery pressure.

The baseline severity of mitral regurgitation is an independent predictor of mortality after TAVI. (23) However, mitral regurgitation does improve after relief of AS in about half of the patients, and a decrease in MR severity is associated with better outcomes. Another potential variable for risk stratification of patients being considered for TAVI is the red cell distribution width (RDW) with a baseline RDW ≥15.5% and a greater increase in RDWover time both found to be independently predictive of mortality after transcatheter aortic valve replacement (TAVR). (24) It is likely that RDW serves as a marker of various comorbidities, including uraemia, malnutrition, iron deficiency and inflammation. The risk of TAVI might be further decreased by avoiding general anaesthesia for this procedure as has been piloted by a group in Germany. (25, 26) A series of 461 patients underwent TAVI with local anaesthesia only, with valve placement guided by fluoroscopy, rather than transoesophageal echocardiography (TOE), with a total combined safety end point, as defined by the Valve Academic Research Consortium consensus statement, of only 12.6%. Rates for specific complications were: death (5%), cerebral complications (2.1%), vascular complications (7.1%), life-threatening bleeding (4.8%), acute kidney injury (1.1%) and pacemaker implantation (12.8%).

Complications

Paravalvular aortic regurgitation after TAVR continues to be a clinical concern, given the association with poor clinical outcomes. (23) In 1432 consecutive patients in the German TAVI registry, in the 201 (15.2%) with more than mild paravalvular AR, 61 (31%) died within 1 year.20 Independent predictors of mortality in those with paravalvular AR were more than mild baseline mitral regurgitation, a higher systolic pulmonary artery pressure and male sex.

Bleeding continues to complicate TAVI procedures, with lifethreatening bleeding occurring in 13%, major bleeding in 9% and minor bleeding in 5% of the 250 patients undergoing TAVI in a recent series. (27) The only independent predictor of lifethreatening bleeding was a transapical access approach.

Transcatheter valves often have a lower transvalvular pressure gradient and large orifice area than a comparable sized surgical bioprosthetic valve. Whether these favourable haemodynamics translate into improved reverse LV remodelling after TAVI has not been established. In a study comparing 25 TAVI and 25 surgical AVR patients matched for gender and AS severity, the 6-month postprocedure decrease in LV volumes and mass, as measured by cardiovascular magnetic resonance, were similar in both groups with baseline myocardial scar and LV volumes being the strongest predictors of reverse remodelling. (28)

Cost effectiveness

As with any newer technology, there is concern about the costs of TAVI for the healthcare system. Using a Markov model with a 10-year horizon, TAVI was cost-effective compared with surgical AVR despite higher procedural costs due to a reduced length and cost of hospital stay in this high-risk cohort. (29) However, these estimates could vary depending on long-term outcomes so that continued attention to this issue is needed.

PROSTHETIC AORTIC VALVES

In a cross-sectional study of over 82 million Medicare beneficiaries, aged 65 years or older, undergoing AVR in the USA from 1999 to 2011, the rate of AVR increased by 1.6% per year, when adjusted for age, sex and race with an adjusted annual decrease in 30-day mortality of 4.1%. (30) Although the number of bioprosthetic valves implanted increased, about 24% of patients aged 85 years and older still received a mechanical valve in 2011, suggesting that improved education about appropriate valve choice is needed among surgeons and cardiologists.

Choice of valve type

In patients undergoing surgical AVR, current guidelines recommend a bioprosthetic valve in patients over 70 years because this valve type is durable in older adults and the risks of long-term anticoagulation with a vitamin-K antagonist are avoided. (1, 2) There was hope that the newer oral anticoagulants might make mechanical valves a more attractive option. Disappointingly, a randomised trial of dabigatran versus warfarin after mechanical mitral valve replacement had to be terminated prematurely due to an excess rate of thromboembolic and bleeding events in patients randomised to dabigatran. (31) Although patients with mechanical aortic valves were not included in this study, it now will require careful consideration whether other clinical trials are appropriate in this population. From a clinical point of view, warfarin currently remains the only accepted antithrombotic therapy for patients with a mechanical heart valve.

Early mortality after AVR in patients receiving a mechanical valve was higher than in those receiving a bioprosthetic valve (unadjusted surgical mortality rates of 1.04% vs 0.57%) in a retrospective analysis of over 66 000 adults over 65 years of age. (32) This difference was confirmed using a mixed effects model for 30-day mortality (adjusted OR, 1.18 (95% CI 1.09 to 1.28; p<0.001); relative risk, 1.16; Number needed to treat (NNT), 121). (32) However, longer-term outcomes were not different either in this study or in a younger population in another retrospective study. In a retrospective cohort analysis of 4259 patients aged 50–69 years who received either a bioprosthetic or mechanical AVR, there was no significant difference in 15-year survival or stroke. (33) As expected, patients with a mechanical valve had a lower likelihood of reoperation but a greater likelihood of major bleeding. (33)

Patient-prosthesis mismatch

Some patients, particularly elderly women, have a small aortic annulus with suboptimal haemodynamics after valve replacement, a condition called patient–prosthesis mismatch (PPM). Previous studies have suggested that PPM is associated with increased mortality, less regression of LV hypertrophy and a higher incidence of heart failure postoperatively, especially in patients with a low EF at baseline. However, the impact of PPM may depend on age at time of valve replacement. (34) In a series of 707 adults undergoing valve replacement for severe AS, PPM was present in 42%, defined as an indexed effective orifice area ≤0.85 cm2/m2. PPM was present in 26% of patients <70 years of age and was associated with decreased survival and increased heart failure in those with LV systolic dysfunction over a median follow-up of 7.3 years. Conversely, although PPM was more common in those over 70 years of age (68%), PPM was only associated with reduced LV mass regression but not with mortality or heart failure in this older age group (Figure 6).

Figure 6. The dimensions of stented surgical bioprostheses. Ventricular and side views of a stented bioprosthesis: (A) outer base ring diameter; (B) inner base ring diameter; (C) prosthesis height and (D) outer sewing ring diameter. (35)

Valve-in-valve procedures

The promising results with the use of transcatheter valve implantation within a failing bioprosthetic valve-in-valve procedure are changing the clinical management of this challenging clinical situation. (35, 36) The first step in clinical evaluation is to distinguish bioprosthetic valve stenosis from PPM, as haemodynamics may be similar, yet stenosis will be improved by valve-in-valve TAVI, whereas PPM will be worsened with further reduction in the effective orifice area by the transcatheter valve. Looking at the time course of changes in valve haemodynamics is helpful because PPM will be evident on the baseline postoperative echocardiography. In contrast, prosthetic valve stenosis will show an increased transvalvular velocity and gradient over time. Direct visualisation of the valve leaflets on TOE or CT imaging also may clarify the diagnosis. In addition, an understanding of the dimensions and design of surgical bioprosthetic valves is needed for proper placement of a valve-in-valve TAVI (Figure 7). The Valve-in-Valve International Data Registry reported a 1-year survival of 83.2% in 459 patients undergoing this procedure. (36) The mean patient age was 77.6 years, 56% were men and all were high risk for repeat surgical AVR. Bioprosthetic valve dysfunction was predominantly stenosis in about 39%, regurgitation in 30% and combined valve dysfunction in the remainder. At 1-month follow-up, 7.6% had died and 1.7% suffered a major stroke, but 92.6% of the surviving patients had a good functional status.

Figure 7. Effect of prosthesis—patient mismatch (PPM) on freedom from death and congestive heart failure (CHF). The effect of PPM on freedom from death and CHF after aortic valve replacement in patients (A) under 70 years of age with normal LV function, (B) under 70 years of age with LV dysfunction, (C) 70 years and older with normal LV function and (D) 70 years and older with LV dysfunction. (34)