CRCM Journal

Introduction

Degenerative aortic stenosis is one of the most common valvular diseases associated with aging. In elderly patients (over 75 years old) the estimated prevalence of aortic stenosis is 12.5% and the estimated prevalence of severe aortic stenosis is 3.4 % [1]. Symptomatic severe aortic stenosis carries an average life expectancy of 2 years and aortic valve replacement (AVR), including surgical bioprosthetic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) are the standards of care [2]. Over 30,000 isolated surgical aortic valve replacements and close to 10,000 TAVRs were performed in the US in 2013, and the TAVR volume has markedly risen to almost 40,000 TAVRs performed in 2016 [3] with an indication for use in both high and intermediate surgical risk patients with severe symptomatic aortic stenosis [4]. The expanding role for surgical bioprosthetic valves and TAVRs raises the important question of valve durability, particularly as it relates to structural valve degeneration, an acquired multifactorial process of leaflet thickening, calcification, and degradation, culminating in valve obstruction and stenosis or leaflet tears and regurgitation. Defining the prevalence of structural valve degeneration (SVD), and by extension bioprosthetic valve durability, proves to be challenging despite efforts to standardize the definition and severity for SVD due to variability in the hemodynamic performance of different types of bioprostheses [5]. Known risk factors for SVD include traditional cardiovascular risk factors (including hypertension, diabetes, end stage renal disease) in addition to younger age of valve implantation, elevated body surface area, tobacco use, and patient prosthesis mismatch [6].

Peripheral artery disease, defined as atherosclerosis of the abdominal aorta, renal and mesenteric arteries, and lower extremity arteries [7], to our knowledge has not been identified as a risk factor for SVD. Lower extremity PAD itself is estimated to impact over 8-12 million Americans with a prevalence of 14.5% in patients aged greater 69 years [8]. Age, tobacco use, and diabetes are among the most strongly associated risk factors [8, 9]. The presence of PAD increases the risk of overall mortality, as well as cardiovascular morbidity and mortality more specifically [10]. Furthermore, progression of PAD is associated with worse cardiovascular outcomes relative to stable disease [11].  Patients with PAD may be asymptomatic or may present with intermittent claudication or critical limb ischemia. The ankle-brachial index is the primary tool utilized for establishing the diagnosis of PAD, with computed tomography angiography, magnetic resonance angiography and contrast arteriography reserved for those patients in whom revascularization is considered [8]. Importantly, despite similarities in age-related prevalence of PAD with degenerative aortic stenosis, there is a lack of robust data examining the potential impact of PAD on SVD in patients with bioprosthetic valves for the treatment of aortic stenosis. 

In this study, we investigated the impact of PAD on SVD in patients who have undergone bioprosthetic valve replacement (SAVR or TAVR) for degenerative severe aortic stenosis. We hypothesize that there is an increased rate of SVD in patients with bioprosthetic valves and PAD versus those without PAD.

Material and Methods

Patient Population

We screened our institutional Surgical Thoracic Society (STS) Adult Cardiac Surgery Database for patients over 65 years of age who had undergone previous surgical aortic valve replacement using a bioprosthetic valve (including SAVR or TAVR) from June 2007 to June 2013 according to predefined inclusion and exclusion criteria. Participants were included if they had echocardiographic data within 3 months of aortic valve intervention, as well as at least 3.5-year clinical and echocardiographic follow-up. Patients who received AVR or TAVR for endocarditis or bicuspid aortic valve or valve-in-valve TAVR were excluded. The study was approved by the Institutional Review Board of the University of Pennsylvania with waiver of consent.

Clinical Data Collection

Clinical data of included patients were retrospectively gathered from the STS database which included age, body mass index, ethnicity, gender, co-morbidities (including hypertension, hyperlipidemia, diabetes mellitus, tobacco use, end stage renal disease, coronary artery disease (CAD)/myocardial infarction), and medications (including aspirin, adenosine diphosphate receptor inhibitors, anticoagulants, and statin).

Echocardiographic Assessment

The echocardiographic assessments at baseline and at follow-up were carried out within 3 months and more than 3.5 years after the initial intervention, respectively. Echocardiographic parameters of bioprosthetic aortic valvular function included mean pressure gradient (MPG), effective orifice area (EOA) and Doppler velocity index (DVI). The MPG was calculated by using the modified Bernoulli formula. The change in MPG was calculated as the gradient at follow-up minus the gradient at baseline. The EOA of the prosthesis was calculated by using the continuity equation. The change in EOA was calculated as the area at follow-up minus the area at baseline. The DVI was also calculated as the ratio between the proximal velocity-time integral in the left ventricular outflow tract (LVOT) and the velocity-time integral through the prosthesis valve. The change in DVI was calculated as the DVI at follow-up minus the DVI at baseline. The origin of prosthetic valve regurgitation was observed by using multiple color Doppler views and a multiparameter integrative approach was used to assess its severity.

SVD Definitions

We used the echocardiographic criteria of stage 2 SVD according to the Valve Academic Research Consortium 3 (VARC-3) consensus statement defined as an increase in mean transvalvular gradient ≥10 mmHg resulting in a MPG of ≥20 mm Hg with a concomitant decrease in the EOA ≥0.3cm2 or ≥25% (and/or decrease in Doppler velocity index ≥0.1 or ≥20%), leading to severe aortic stenosis according with clinical symptoms, and/or new occurrence or increase of at least 1 grade of intra-prosthetic regurgitation leading to moderate or greater aortic regurgitation[5]. We also included patients who underwent re-do aortic valve replacement due to SVD.

PAD Assessment and Grouping

Patients were included in the PAD groups as determined by STS database. As a confirmatory measure, patients were randomly selected to undergo chart review to identify the presence of PAD. Presence of PAD was identified by a history of prior peripheral revascularization, claudication with positive ankle -brachial index (ABI < 0.9), or imaging (computed tomographic angiography, magnetic resonance angiography or angiography) suggestive of PAD.  Involved subjects were divided into PAD group and nonPAD group.

Statistical Analysis

Statistical analysis involved use of IBM SPSS Statistics version 21.0 software (IBM Inc., New York, USA), Continuous variables are described as mean ± standard deviation (SD) if they were normally distributed, or median (interquartile range) if not. Categorical variables are described as number (percent). Group comparisons were analyzed with the Student’s t-test or Wilcoxon rank sum test for continuous variables and the chi-square test or Fisher exact test for categorical variables. Two tailed P < 0.05 was considered statistically significant.

Results

Clinical characteristics

154 patients were identified to meet the inclusion criteria and did not meet the exclusion criteria (Figure 1). The mean age was 79.7 ± 7.3 years (range 65 - 92); 93 were males. 82 patients had PAD and 72 patients did not. There were no significant differences in the following baseline characteristics between the PAD and non-PAD patients: age, sex, race, body mass index, tobacco use, hyperlipidemia, diabetes, renal failure, dialysis, prior myocardial infarction, and medication use (including aspirin, adenosine diphosphate inhibitor, statin, and warfarin) (Table 1). Rates of hypertension and CAD burden were statistically different between the two groups. Eighty patients (97.6%) had hypertension in PAD group and 63 (87.5%) in non-PAD group (p<0.05). In the PAD group, there were 19 patients with triple-vessel CAD (23.2%), 20 patients with two-vessel disease (24.4%), 11 patients with singlevessel disease (13.4%) and 32 patients with non-significant CAD (39.0%), while in the non-PAD group, 7 patients had triple-vessel disease (9.7%), 12 patients had two-vessel disease (16.7%), 5 patients had single-vessel disease (6.9%) and 48 patients had nonsignificant CAD (66.7%).

Figure 1. Flowchart describing process of patient selection.

Table 1. General clinical characteristics in two groups.

Differences in echocardiographic parameters between PAD group and Non-PAD group

Transthoracic echocardiographic examinations were performed within 3 months of the index aortic valve replacement (SAVR or TAVR) and at least 3.5 years post procedure.  The median follow-up was similar [51 (49-66) months vs. 51 (49-62) months, p > 0.05) (Table 2). The two groups had no obvious differences in MPG, DVI, and EOA at baseline post-operation, or at follow-up (all p > 0.05) (Table 2). The changes in MPG, DVI, and EOA were also the same between both groups (all p > 0.05) (Table 2). The left ventricular ejection fraction (EF) at baseline post-operation was different between the two groups: it was lower in the PAD group than that in the non-PAD group [60.0% (55.0%-67.5%) vs. 65.0% (56.2%-70.0%), p=0.04] (Table 2). The EF at follow-up and the changes of EF were not significantly different between groups (p > 0.05) (Table 2).

Table 2 Valve gradients and LV function at baseline post-op and at follow up Values are mean ± SD or median (interquartile range). MPGpo: mean pressure gradient at post-operation; MPGfu: mean pressure gradient at follow-up; ΔMPG: the change of mean pressure gradient; EOApo: effective orifice area at post-operation; EOAfu: effective orifice area at follow-up; ΔEOA: the change of effective orifice area; DVIpo: Doppler velocity index at post-operation; DVIfu: Doppler velocity index at follow-up; ΔDVI: the change of Doppler velocity index; EFpo: ejection fraction at post-operation; EFfu: ejection fraction at follow-up; ΔEF: the change of ejection fraction.

Structural valve degeneration

At follow-up, there was a statistically significant difference in the rates of clinically relevant SVD in the PAD patients versus nonPAD patients [6 (7.3%) vs. 0 (0.0%), p = 0.03]. The echocardiographic parameters of bioprosthetic aortic valvular function of 6 patients with clinically relevant SVD are detailed in (Table 3). One example of initial prosthetic valve gradients and follow-up high gradients on echocardiography is shown in (Figure 2). Of note, not all the echocardiographic parameters were available for each patient and structural valve degeneration was identified based on all available data in addition to subsequent redo valve replacement for SVD.

Table 3 Echocardiographic parameters of bioprosthetic aortic valvular function of 6 patients with clinically relevant SVD. MPGpo: mean pressure gradient at post-operation; MPGfu: mean pressure gradient at follow-up; EOApo: effective orifice area at post-operation; EOAfu: effective orifice area at follow-up; DVIpo: Doppler velocity index at post-operation; DVIfu: Doppler velocity index at followup; ARpo: Aortic valvular regurgitation at post-operation (only included if moderate to severe or greater). ARfu: Aortic valvular regurgitation at follow-up; viv: valve-in-valve.