Subclinical valve leaflet thrombosis following bioprosthetic aortic valve replacement.

PURPOSE OF REVIEW: Subclinical leaflet thrombosis (SLT) is often an incidental finding characterized by a thin layer of thrombus involving one, two or three leaflets, with typical appearance on multi-detector computed tomography (MDCT) of hypo-attenuating defect at the aortic side of the leaflet, also called hypo-attenuating leaflet thickening (HALT). SLT may occur following both transcatheter aortic replacement (TAVR) or biological surgical aortic valve replacement (SAVR). The aim of this review is to present an overview of the current state of knowledge on the incidence, diagnosis, clinical impact, and management of SLT following TAVR or SAVR. RECENT FINDINGS: SLT occurs in 10-20% of patients following TAVR and is somewhat more frequent than following SAVR (5-15%). SLT may regress spontaneously without treatment in about 50% of the cases but may also progress to clinically significant valve thrombosis in some cases. Oral anticoagulation with vitamin K antagonist is reasonable if SLT is detected by echocardiography and/or MDCT during follow-up and is generally efficient to reverse SLT. SLT is associated with mild increase in the risk of stroke but has no impact on survival. SLT has been linked with accelerated structural valve deterioration and may thus impact valve durability and long-term outcomes. SUMMARY: SLT is often an incidental finding on echocardiography or MDCT that occurs in 10-20% of patients following TAVR or 5-15% following biological SAVR and is associated with a mild increase in the risk of thrombo-embolic event with no significant impact on mortality but may be associated with reduced valve durability.

Situations of anomie and the health workforce crisis: Policy implications of a socially sensitive and inclusive approach to human resources.

Health systems in most jurisdictions are facing an unprecedented workforce crisis, manifesting as labour shortages, high staff turnover, and increasing rates of absenteeism and burnout. These issues affect professional and occupational groups in both health and social care and individuals at early and later stages of their career. The intensity and pervasiveness of the crisis suggests that it is a multicausal phenomenon. Studies have focused on the relationship between working environments and worker satisfaction and well-being. However, these are of limited use in understanding the deeper mechanisms behind the large-scale workforce crisis. The subjective experience of work, while rooted in a particular work context, is also shaped by broader social and cultural phenomena that put social norms and individuals' ability to conform to them in tension. The concept of anomie, initially developed by Durkheim and redefined by Merton, focuses on the way social norms that guide conduct and aspirations lose influence and become incompatible with each other or unsuited to contemporary work contexts. Understanding the workforce crisis from the perspective of anomie enables the development and implementation of novel policies based on co-production strategies where concerned publics engage collaboratively in framing the problem and searching for solutions.

In vitro Doppler versus catheter transvalvular pressure gradients in balloon-expandable versus self-expanding transcatheter aortic valves.

OBJECTIVES: The objective of this in vitro study was to compare Doppler versus catheter transvalvular pressure gradients (TPG) in third generations balloon-expandable (BE) versus self-expanding (SE) transcatheter heart valves (THV). BACKGROUND: TPG is a key parameter to assess and follow valve hemodynamic function following transcatheter aortic valve implantation (TAVI). It remains uncertain and debated whether, and to which extent, TPGs differ according to the type of THV, that is, BE versus SE and to the method used for TPG measurement, that is, Doppler echocardiography versus cardiac catheterization. METHODS: The CoreValve EVOLUT PRO 26 mm and the SAPIEN 3 23 mm THVs were tested in a left heart simulator using a 21 mm aortic annulus under following conditions: heart rate: 70 bpm, mean aortic pressure: 100 mmHg, stroke volume: 30, 70 and 100 ml. Mean TPGs were measured by continuous-wave Doppler and by micro-tip pressure catheters positioned in the left ventricle and at 50 mm downstream to the tip of the THV leaflets. RESULTS: Doppler TPGs (9.5 ± 3.9 mmHg) were on average 40.5 ± 13.9% higher (p < 0.001) than catheter TPGs (6.3 ± 3.4 mmHg). Both Doppler and catheter TPGs were lower (p = 0.003) in the SE versus BE THVs (Doppler: 8.7 ± 3.5 vs. 10.7 ± 4.6; catheter: 5.0 ± 1.7 mmHg vs. 7.1 ± 2.2). The Doppler versus catheter difference in TPG increased with the higher flow conditions. The Doppler versus catheter difference in TPG was similar in BE versus SE THVs (3.6 ± 1.1 vs. 3.7 ± 1.4 mmHg or 42 ± 9 vs. 47 ± 9%; p = 0.58) overall and in each flow conditions. CONCLUSION: The Doppler TPGs are, on average, 40% higher than the catheter TPGs for both BE and SE THVs. The SE THV had lower Doppler and catheter TPGs compared to the BE THV, at normal and high flow states. The absolute and percent differences between Doppler versus catheter TPGs were similar in BE versus SE THVs.

Metabolic Syndrome Exacerbates Pulmonary Hypertension due to Left Heart Disease.

RATIONALE: Pulmonary hypertension (PH) due to left heart disease (LHD), or group 2 PH, is the most prevalent form of PH worldwide. PH due to LHD is often associated with metabolic syndrome (MetS). In 12% to 13% of cases, patients with PH due to LHD display vascular remodeling of pulmonary arteries (PAs) associated with poor prognosis. Unfortunately, the underlying mechanisms remain unknown; PH-targeted therapies for this group are nonexistent, and the development of a new preclinical model is crucial. Among the numerous pathways dysregulated in MetS, inflammation plays also a critical role in both PH and vascular remodeling. OBJECTIVE: We hypothesized that MetS and inflammation may trigger the development of vascular remodeling in group 2 PH. METHODS AND RESULTS: Using supracoronary aortic banding, we induced diastolic dysfunction in rats. Then we induced MetS by a combination of high-fat diet and olanzapine treatment. We used metformin treatment and anti-IL-6 (interleukin-6) antibodies to inhibit the IL-6 pathway. Compared with sham conditions, only supracoronary aortic banding+MetS rats developed precapillary PH, as measured by both echocardiography and right/left heart catheterization. PH in supracoronary aortic banding+MetS was associated with macrophage accumulation and increased IL-6 production in lung. PH was also associated with STAT3 (signal transducer and activator of transcription 3) activation and increased proliferation of PA smooth muscle cells, which contributes to remodeling of distal PA. We reported macrophage accumulation, increased IL-6 levels, and STAT3 activation in the lung of group 2 PH patients. In vitro, IL-6 activates STAT3 and induces human PA smooth muscle cell proliferation. Metformin treatment decreased inflammation, IL-6 levels, STAT3 activation, and human PA smooth muscle cell proliferation. In vivo, in the supracoronary aortic banding+MetS animals, reducing IL-6, either by anti-IL-6 antibody or metformin treatment, reversed pulmonary vascular remodeling and improve PH due to LHD. CONCLUSIONS: We developed a new preclinical model of group 2 PH by combining MetS with LHD. We showed that MetS exacerbates group 2 PH. We provided evidence for the importance of the IL-6-STAT3 pathway in our experimental model of group 2 PH and human patients.

Global health and innovation: A panoramic view on health human resources in the COVID-19 pandemic context.

While policy-makers in many jurisdictions are paying increasing attention to health workforce issues, human resources remain at best only partially aligned with population health needs. This paper explores the governance of human resources during the pandemic, looking at the Quebec health system as a revelatory case. We identify three issues related to health human resource (HHR) policies: working conditions, recognition at work and scope of practice. We empirically probe these issues based on an analysis of popular media, policy reports and participant observation by the lead authors in various forums and research projects. Using an integrated model of HHR, we identify major vulnerabilities in this domain. Persistent labour shortages, endemic deficiencies in working environments and inequity across occupational categories limit the ability to address critical HHR issues. We propose three ways to eliminate HHR vulnerabilities: reorganize work through participatory initiatives, implement joint policy making to rebalance power across the health workforce, and invest in the development of capacities at all system levels.

Rate, Timing, Correlates, and Outcomes of Hemodynamic Valve Deterioration After Bioprosthetic Surgical Aortic Valve Replacement.

BACKGROUND: The incidence of structural valve deterioration after bioprosthesis (BP) aortic valve replacement (AVR) established on the basis of reoperation may substantially underestimate the true incidence. The objective is to determine the rate, timing, correlates, and association between hemodynamic valve deterioration (HVD) and outcomes assessed by Doppler echocardiography after surgical BP AVR. METHODS: A total of 1387 patients (62.2% male, 70.5±7.8 years of age) who underwent BP AVR were included in this retrospective study. Baseline echocardiography was performed at a median time of 4.1 (1.3-6.5) months after AVR. All patients had an echocardiographic follow-up ≥2 years after AVR (926 at least 5 years and 385 at least 10 years). HVD was defined by Doppler assessment as a ≥10 mm Hg increase in mean gradient or worsening of transprosthetic regurgitation ≥1/3 class. HVD was classified according to the timing after AVR: "very early," during the first 2-years; "early," between 2 and 5 years; "midterm," between 5 and 10 years; and "long-term," >10 years. RESULTS: A total of 428 patients (30.9%) developed HVD. Among these patients, 52 (12.0%) were classified as "very early," 129 (30.1%) as "early," 158 (36.9%) as "midterm," and 89 (20.8%) as "long-term" HVD. Factors independently associated with HVD occurring within the first 5 years after AVR were diabetes mellitus ( P=0.01), active smoking ( P=0.01), renal insufficiency ( P=0.01), baseline postoperative mean gradient ≥15 mm Hg ( P=0.04) or transprosthetic regurgitation ≥mild ( P=0.04), and type of BP (stented versus stentless, P=0.003). Factors associated with HVD occurring after the fifth year after AVR were female sex ( P=0.03), warfarin use ( P=0.007), and BP type ( P<0.001). HVD was independently associated with mortality (hazard ratio, 2.18; 95% CI, 1.86-2.57; P<0.001). CONCLUSIONS: HVD as identified by Doppler echocardiography occurred in one third of patients and was associated with a 2.2-fold higher adjusted mortality. Diabetes mellitus and renal insufficiency were associated with early HVD, whereas female sex, warfarin use, and stented BPs (versus stentless) were associated with late HVD.

Biomarkers of aortic bioprosthetic valve structural degeneration.

PURPOSE OF REVIEW: Bioprosthetic valves are now used for the majority of surgical aortic valve replacements and for all transcatheter aortic valve replacements. However, bioprostheses are subject to structural valve deterioration (SVD) and have, therefore limited durability. RECENT FINDINGS: Clinical, imaging, and circulating biomarkers may help to predict or indicate the presence of bioprosthetic valve SVD. The most important biomarkers of SVD includes: patient-related clinical biomarkers, such as diabetes and renal failure; valve-related biomarkers, such as absence of antimineralization process and severe prosthesis-patient mismatch; imaging biomarkers: the presence of valve leaflet mineralization on multidetector computed tomography or sodium fluoride uptake on positron emission tomography; and circulating biomarkers including: increased levels of HOMA index, ApoB/ApoA-I ratio, PCSK9, Lp-PLA2, phosphocalcic product. The assessment of these biomarkers may help to enhance risk stratification for SVD following AVR and may contribute to open novel pharmacotherapeutic avenues for the prevention of SVD. SUMMARY: SVD may affect all bioprostheses after aortic valve replacement, and is the main cause of bioprosthetic valve failure and reintervention during the follow-up. Comprehensive assessment of clinical, imaging, and circulating biomarkers associated with earlier SVD could help strengthen the follow-up in high-risk patients and provide novel pharmacologic therapeutic strategies.

Sex-Related Discordance Between Aortic Valve Calcification and Hemodynamic Severity of Aortic Stenosis: Is Valvular Fibrosis the Explanation?

RATIONALE: Calcific aortic stenosis (AS) is characterized by calcium deposition in valve leaflets. However, women present lower aortic valve calcification loads than men for the same AS hemodynamic severity. OBJECTIVE: We, thus, aimed to assess sex differences in aortic valve fibrocalcific remodeling. METHODS AND RESULTS: One hundred and twenty-five patients underwent Doppler echocardiography and multidetector computed tomography within 3 months before aortic valve replacement. Explanted stenotic tricuspid aortic valves were weighed, and fibrosis degree was determined. Sixty-four men and 39 women were frequency matched for age, body mass index, hypertension, renal disease, diabetes mellitus, and AS severity. Mean age (75±9 years), mean gradient (41±18 mm Hg), and indexed aortic valve area (0.41±0.12 cm2/m2) were similar between men and women (all P≥0.18). Median aortic valve calcification (1973 [1124-3490] Agatston units) and mean valve weight (2.36±0.99 g) were lower in women compared with men (both P<0.0001). Aortic valve calcification density correlated better with valve weight in men (r2=0.57; P<0.0001) than in women (r2=0.26; P=0.0008). After adjustment for age, body mass index, aortic valve calcification density, and aortic annulus diameter, female sex was an independent risk factor for higher fibrosis score in AS valves (P=0.003). Picrosirius red staining of explanted valves showed greater amount of collagen fibers (P=0.01), and Masson trichrome staining revealed a greater proportion of dense connective tissue (P=0.02) in women compared with men. CONCLUSIONS: In this series of patients with tricuspid aortic valve and similar AS severity, women have less valvular calcification but more fibrosis compared with men. These findings suggest that the pathophysiology of AS and thus potential targets for drug development may be different according to sex.

New understanding of primary health care nurse practitioner role optimisation: the dynamic relationship between the context and work meaning.

BACKGROUND: Optimising health professionals' contribution is an essential step in effective and efficient health human resources utilisation. However, despite the considerable efforts made to implement advanced practice nursing roles, including those in primary care settings (PHCNP), the optimisation of these roles remains variable. In this investigation, we report on the subjective work experience of a group of PHCNPs in the province of Quebec (Canada). METHODS: We used Giddens' structuration theory to guide our study given its' facilitation of the understanding of the dynamic between structural constraints and actors' actions. Using a qualitative descriptive study design, and specifically both individual and focus group interviews, we conducted our investigation within three health care regions in Quebec during 2016-2017. RESULTS: Forty-one PHCNPs participated. Their descriptions of their experience fell into two general categories. The first of these, their perception of others' inadequate understanding and valuing of their role, included the influence of certain work conditions, perceived restrictions on professional autonomy and the feeling of being caught between two professional paradigms. The second category, the PHCNPs' sense of engagement in their work, included perspectives associated with the specific conditions in which their work is situated, for example, the fragility of the role depending on the particular clinic/s in which they work or on the individuals with whom they work. This fragility was also linked with certain health care reforms that had been implemented in Quebec (e.g., legislation requiring greater physician productivity). CONCLUSION: Several new insights emerged, for example, the sense of role fragility being experienced by PHCNPs. The findings suggest an overarching link between the work context, the meaning attributed by PHCNPs to their work and their engagement. The optimisation of their role at the patient care level appears to be influenced by elements at the organisational and health system context levels. It appears that role optimisation must include the establishment of work environments and congruent health context structures that favour the implementation and deployment of new professional roles, work engagement, effective collaboration in interprofessional teams, and opportunities to exercise agency. Further research is necessary to evaluate initiatives that endeavour to achieve these objectives.

Advanced practice nursing: Qualitative study of implications for family physicians' perceptions of their own work.

OBJECTIVE: To explore family physicians' perspectives on how best to exercise their role relative to that of primary health care nurse practitioners (PHCNPs). DESIGN: Qualitative case study. SETTING: Three Quebec health care regions. PARTICIPANTS: Sixteen physicians participated. To be eligible, family physicians were required to have worked with at least 1 PHCNP for a minimum of 6 months. METHODS: Semistructured individual and focus group interviews. MAIN FINDINGS: The implementation of the PHCNP role can be associated with considerable redesign of family physicians' habitual ways of functioning and with important transformations in their role within primary care teams, which can lead these professionals to reflect upon the meaning of their work. The physicians identified the following 4 elements that influenced their views: the nature of follow-up possible with patients, sharing the scope of practice, the patient profile, and new positive work experiences. CONCLUSION: The evolution of family physicians' role in the face of the PHCNP role must be situated within a discussion about the overall organization of care provision to patients and is not as straightforward as simply defining task division. This implementation also must take into account the frequently highly demanding context in which family physicians practise. Greater understanding is needed about contextual conditions that will facilitate physicians' practice within multidisciplinary teams, including the nature of, and interaction among, micro-, meso- and macro-level elements.

Dilemma in the therapeutic management of low-gradient aortic stenosis.

PURPOSE OF REVIEW: Grading of aortic stenosis is essential in aortic stenosis management patients. However, despite clear thresholds provided in the guidelines, up to 30% of patients have discordant grading of aortic stenosis. The management of patients with low gradients/velocity despite tight aortic valve area is challenging. RECENT FINDINGS: Recent studies demonstrated that patients with or without low flow may have a severe aortic stenosis despite a low gradient. Moreover, aortic valve replacement has been shown to improve outcome in low-gradient aortic stenosis patients with or without low flow. Finally, measurement of aortic valve calcification by multidetector computed tomography is an important tool to assess aortic stenosis severity in these patients. SUMMARY: The presence of a low gradient/velocity despite a tight aortic valve area could be linked to low ejection fraction or low flow with preserved ejection fraction but also with normal flow and normal ejection fraction. In each situation, aortic stenosis could be truly severe or pseudosevere, and the severity of aortic stenosis has to be accurately evaluated for clinical decision-making. Nowadays, two types of interventions are available: surgical and transcatheter aortic valve replacement, whereas conservative management should be considered as a palliative treatment in patients with proven severe aortic stenosis and symptoms or left ventricle dysfunction.

Incidence, risk factors, clinical impact, and management of bioprosthesis structural valve degeneration.

PURPOSE OF REVIEW: Structural valve deterioration is the major cause of bioprosthesis failure and is increasing over time. We present an overview of incidence, mechanisms, predictors, clinical impact, and management of bioprosthetic valve structural degeneration. RECENT FINDINGS: Early degeneration caused by calcification and destruction of connective tissue of the prosthesis is controlled by multiple mechanisms, from mechanical stress to infiltration of lipids and inflammatory cells, and activation of the immune system. Despite major improvements in valve design and surgical procedures, the pathology is still the main limiting factor to the long-term durability. Appropriate selection of the model and size of bioprosthesis as well as proper medical management and follow-up after valve replacement are essential for optimal prevention, detection, and management of structural valve deterioration. Currently, redo open-heart surgery is the most frequently used approach to treat structural valve deterioration. The transcatheter valve-in-valve procedure, however, is a valuable alternative to surgery for high-risk patients. SUMMARY: Structural valve deterioration is responsible for significant morbidity and mortality after valve replacement. This multifactorial pathology is the main cause of valve re-intervention during follow-up. Although redo surgery is still the most frequently used intervention to treat valve structural failure, the transcatheter valve-in-valve procedure is rapidly expanding.

Subclinical bioprosthetic aortic valve thrombosis: clinical and translational implications.

PURPOSE OF REVIEW: A recently published study has alerted the cardiovascular community to the existence of a significant and previously unrecognized risk of subclinical valve thrombosis following implantation of surgical and catheter-based bioprosthetic valves. The purpose of this article is to review our current understanding of this new clinical entity and to identify unanswered questions and areas for future research. RECENT FINDINGS: Subclinical bioprosthetic valve thrombosis (BPVT) is a more common phenomenon than previously appreciated. It appears that the incidence of BPVT is higher following transcatheter aortic valve replacement compared with surgical aortic valve replacement. Four-dimensional computed tomography (CT) is the most sensitive imaging modality for detection of leaflet immobility and subclinical BPVT. Certain echocardiographic findings, such as increasing transaortic gradients, increased cusp thickness and abnormal cusp mobility, predict the presence of BPVT on four-dimensional CT. There is a growing body of evidence linking subclinical BPVT with premature valvular hemodynamic deterioration and structural valve degeneration. Furthermore, subclinical leaflet thrombosis may constitute a nidus for unrecognized subacute cerebral or other thromboembolic events. Oral anticoagulation seems effective in both the prevention and treatment of BPVT. SUMMARY: Subclinical valve thrombosis is an important and underappreciated cause of early bioprosthetic valve failure. Although several recent studies have improved our understanding of this newly recognized clinical entity, a number of questions remain unanswered. Further studies are warranted to elucidate the true incidence of subclinical BPVT, its clinical consequences, as well as the optimal antithrombotic regimen following bioprosthetic valve implantation. The subgroups of patients at highest risk of BPVT will need to be identified for risk stratification purposes. Several ongoing clinical trials will shed some light on these important issues.

Carbonic anhydrase XII in valve interstitial cells promotes the regression of calcific aortic valve stenosis.

AIMS: Calcific aortic valve stenosis (CAVS) is the most common heart valve disease. In the present work we sought to determine the reversibility of mineralization in the aortic valve. METHODS AND RESULTS: By using in vitro analyses we found that valve interstitial cells (VICs) have the ability to resorb minerals. We documented that agonist of P2Y2 receptor (P2Y2R) promoted the expression of carbonic anhydrase XII (CAXII) at the cell membrane of VICs, whereby minerals are resorbed. P2Y2R-mediated mineral resorption was corroborated by using mouse VICs isolated from wild type and P2Y2R(-/-) mice. Measurements of extracellular pH (pHe) by using core-shell nanosensors revealed that P2Y2R-mediated CAXII export to the cell membrane led to an acidification of extracellular space, whereby minerals are resorbed. In vivo, we next treated LDLR(-/-)/ApoB(100/100)/IGF2 mice, which had developed CAVS under a high-fat/high-sucrose diet for 8 months, with 2-thioUTP (a P2Y2R agonist) or saline for the next 2 months. The administration of 2-thioUTP (2mg/kg/day i.p.) reduced the mineral volume in the aortic valve measured with serial microCT analyses, which improved hemodynamics and reduced left ventricular hypertrophy (LVH). Examination of leaflets at necropsy confirmed a lower level of mineralization and fibrosis along with higher levels of CAXII in mice under 2-thioUTP. In another series of experiment, the administration of acetazolamide (a CA inhibitor) prevented the acidification of leaflets and the regression of CAVS induced by 2-thioUTP in LDLR(-/-)/ApoB(100/100)/IGF2 mice. CONCLUSION: P2Y2R-mediated expression of CAXII by VICs acidifies the extracellular space and promotes the regression of CAVS.

Paradoxical low-flow, low-gradient aortic stenosis despite preserved left ventricular ejection fraction: new insights from weights of operatively excised aortic valves.

AIMS: We reported that patients with small aortic valve area (AVA) and low flow despite preserved left ventricular ejection fraction (LVEF), i.e. 'paradoxical' low flow (PLF), have worse outcomes compared with patients with normal flow (NF), although they generally have a lower mean gradient (MG). The aortic valve weight (AVW) excised at the time of valve replacement is a flow-independent marker of stenosis severity. The objective of this study was to compare the AVW of patients with PLF and MG<40 mmHg with the AVW of patients with NF and MG≥40 mmHg. METHODS AND RESULTS: We recruited 250 consecutive patients undergoing valve replacement (Cohort A) for severe stenosis. Among them, 33 (13%) were in PLF [LVEF > 50% but stroke volume index (SVi) ≤ 35 mL/m(2)] with MG < 40 mmHg (PLF-LG group) and 105 (42%) were in NF (LVEF > 50% and SVi > 35 mL/m(2)) with MG ≥ 40 mmHg (NF-HG group). Despite a much lower MG (29 ± 7 vs. 53 ± 10 mmHg; P < 0.0001), patients in the PLF-LG group had a similar AVA (0.73 ± 0.12 vs. 0.69 ± 0.13; P = 0.19) compared with those in the NF-HG group. The AVW [median (interquartile): 1.90 (1.63-2.50) vs. 2.60 (1.66-3.32)] and prevalence of bicuspid phenotype (15 vs. 42%) were lower in the PLF-LG group than in the NF-HG group. However, AVWs analysed separately in the tricuspid and bicuspid valves were similar in both groups [tricuspid valves: 1.80 (1.63-2.50) vs. 2.30 (1.58-3.00) g; P = 0.26 and bicuspid valves: 2.72 (1.73-3.61) vs. 2.60 (2.10-3.55) g; P = 0.93]. When using cut-point values of AVW established in another series of non-consecutive patients (n = 150, Cohort B) with NF and concordant Doppler-echocardiographic findings, we found that the percentage of patients with evidence of severe stenosis in Cohort A was 70% in patients with PLF-LG and 86% in patients with NF-HG. CONCLUSION: The aortic valve weight data reported in this study provide evidence that a large proportion of patients with PLF and low-gradient have a severe stenosis and that the gradient may substantially underestimate stenosis severity in these patients. A multi-parametric approach including all Doppler-echocardiographic parameters of valve function as well as other complementary diagnostic tests may help correctly identify these patients.

Angiotensin receptor blockers are associated with reduced fibrosis and interleukin-6 expression in calcific aortic valve disease.

BACKGROUND: Calcific aortic valve disease (CAVD) is a chronic disorder characterized by the mineralization of the aortic valve and involving fibrosis. OBJECTIVES: In this work we sought to determine if the fibrotic component of the remodeling process of CAVD was related to the use of angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs). METHODS: In 477 patients with CAVD, the aortic valve was examined by histology. A semiquantitative score of fibrosis was generated and associations with clinical/cardiometabolic variables examined. In a subset of 103 patients the aortic valve was available to study the infiltration by inflammatory cells and expression of interleukin-6 (IL-6) by quantitative real-time PCR. RESULTS: The fibrosis score of the aortic valve was independently related to the hemodynamic severity of CAVD measured by echocardiography. The fibrotic score of the aortic valve was also related to the expression of IL-6. The use of ARBs but not of ACEi was associated with a lower fibrosis score of the aortic valve even after correction for covariates. In addition, patients under ARBs had lower aortic valve inflammation and expression of IL-6. CONCLUSIONS: These findings suggest that ARBs may alter the fibrotic process of the aortic valve in CAVD, possibly by lowering tissue inflammation.

Leaflet Mechanical Stress in Different Designs and Generations of Transcatheter Aortic Valves: An in Vitro Study.

Background: It is unknown whether bioprostheses used for transcatheter aortic valve implantation will have similar long-term durability as those used for surgical aortic valve replacement. Repetitive mechanical stress applied to the valve leaflets, particularly during diastole, is the main determinant of structural valve deterioration. Leaflet mechanical stress cannot be measured in vivo. The objective of this in vitro/in silico study was thus to compare the magnitude and regional distribution of leaflet mechanical stress in old vs new generations of self-expanding (SE) vs balloon expandable (BE) transcatheter heart valves (THVs). Methods: A double activation simulator was used for in vitro testing of two generations of SE THV (Medtronic CoreValve 26 mm and EVOLUT PRO 26 mm) and two generations of BE THV (Edwards SAPIEN 23 mm vs SAPIEN-3 23 mm). These THVs were implanted within a 21-mm aortic annulus. A noncontact system based on stereophotogammetry and digital image correlation with high spatial and temporal resolution (2000 img/sec) was used to visualize the valve leaflet motion and perform the three-dimensional analysis. A finite element model of the valve was developed, and the leaflet deformation obtained from the digital image correlation analysis was applied to the finite element model to calculate local leaflet mechanical stress during diastole. Results: The maximum von Mises leaflet stress was higher in early vs new THV generation (p < 0.05) and in BE vs SE THV (p < 0.05): early generation BE: 2.48 vs SE: 1.40 MPa; new generation BE: 1.68 vs SE: 1.07 MPa. For both types of THV, the highest values of leaflet stress were primarily observed in the upper leaflet edge near the commissures and to a lesser extent in the mid-portion of the leaflet body, which is the area where structural leaflet deterioration most often occurs in vivo. Conclusions: The results of this in vitro/in silico study suggest that: i) Newer generations of THVs have ∼30% lower leaflet mechanical stress than the early generations; ii) For a given generation, SE THVs have lower leaflet mechanical stress than BE THVs. Further studies are needed to determine if these differences between new vs early THV generations and between SE vs BE THVs will translate into significant differences in long-term valve durability in vivo.

Durability of transcatheter aortic valve implantation.

Transcatheter aortic valve implantation (TAVI) is now utilised as a less invasive alternative to surgical aortic valve replacement (SAVR) across the whole spectrum of surgical risk. Long-term durability of the bioprosthetic valves has become a key goal of TAVI as this procedure is now considered for younger and lower-risk populations. The purpose of this article is to present a state-of-the-art overview on the definition, aetiology, risk factors, mechanisms, diagnosis, clinical impact, and management of bioprosthetic valve dysfunction (BVD) and failure (BVF) following TAVI with a comparative perspective versus SAVR. Structural valve deterioration (SVD) is the main factor limiting the durability of the bioprosthetic valves used for TAVI or SAVR, but non-structural BVD, such as prosthesis-patient mismatch and paravalvular regurgitation, as well as valve thrombosis or endocarditis may also lead to BVF. The incidence of BVF related to SVD or other causes is low (<5%) at midterm (5- to 8-year) follow-up and compares favourably with that of SAVR. The long-term follow-up data of randomised trials conducted with the first generations of transcatheter heart valves also suggest similar valve durability in TAVI versus SAVR at 10 years, but these trials suffer from major survivorship bias, and the long-term durability of TAVI will need to be confirmed by the analysis of the low-risk TAVI versus SAVR trials at 10 years.

Multimarker Approach to Improve Risk Stratification of Patients Undergoing Transcatheter Aortic Valve Implantation.

Background: A blood multimarker approach may be useful to enhance risk stratification in patients undergoing TAVI. Objectives: The objective of this study was to determine the prognostic value of multiple blood biomarkers in transcatheter aortic valve implantation (TAVI) patients. Methods: In this prospective study, several blood biomarkers of cardiovascular function, inflammation, and renal function were measured in 362 patients who underwent TAVI. The cohort was divided into 3 groups according to the number of elevated blood biomarkers (ie, ≥ median value for the whole cohort) for each patient before the procedure. Survival analyses were conducted to evaluate the association between blood biomarkers and risk of adverse event following TAVI. Results: During a median follow-up of 2.5 (IQR: 1.9-3.2) years, 34 (9.4%) patients were rehospitalized for heart failure, 99 (27%) patients died, and 113 (31.2%) met the composite endpoint of all-cause mortality or heart failure rehospitalization. Compared to patients with 0 to 3 elevated biomarkers (referent group), those with 4 to 7 and 8 to 9 elevated biomarkers had a higher risk of all-cause mortality (HR: 1.54 [95% CI: 0.84-2.80], P = 0.16, and HR: 2.81 [95% CI: 1.53-5.15], P < 0.001, respectively) and of the composite endpoint (HR: 1.65 [95% CI: 0.95-2.84], P = 0.07, and HR: 2.67 [95% CI: 1.52-4.70] P < 0.001, respectively). Moreover, adding the number of elevated blood biomarkers into the clinical multivariable model provided significant incremental predictive value for all-cause mortality (Net Reclassification Index = 0.71, P < 0.001). Conclusions: An increasing number of elevated blood biomarkers is associated with higher risks of adverse clinical outcomes following TAVI. The blood multimarker approach may be helpful to enhance risk stratification in TAVI patients.