Challenges and opportunities in valvular heart disease: From molecular mechanisms to the community

Graphical Abstract

Global burden of valvular heart disease

Valvular heart disease (VHD) takes a central stage in contemporary cardiology due to population aging and immense progress in percutaneous approaches to its treatment. VHD continues to be a major cause of death and suffering in both developed, and low- and middle-income countries. In the United States, moderate-to-severe VHD occurs in 13.2% of people aged 75 or older, with 2.8% for symptomatic calcific aortic stenosis, and 9.3% for mitral valve regurgitation.¹ The right-sided pulmonary and tricuspid valves can also develop disease, though they represent only 25% of all VHD-associated deaths.² Worldwide, rheumatic heart disease affects 33.4 million individuals in endemic regions, progressing from childhood and increasing maternal mortality.³ Strikingly, there are no effective nor approved medicines for any form of VHD. The only available therapy remains valve repair or replacement, which are highly specialized, invasive, and costly procedures primarily performed in late-stage disease and often unavailable in developing countries.

Imaging has been crucial in revealing VHD mechanisms through assessment of morphologic and functional changes. In one of its most powerful scientific applications, imaging provides a window into basic cellular, molecular, and biomechanical mechanisms of VHD and valvular (patho)physiological adaptation. During both embryonic development and in the adult heart, valves reciprocally adapt and, through their (dys)function, augment cardiac remodeling.

Heart valves perform extremely crucial functions, which translate into clinically relevant end points such as survival and quality of life.⁴ These functions require a very specialized structure at molecular, cellular, tissue and organ levels.⁵ The rising disease burden and lack of understanding of the differential pathophysiological mechanisms underlying VHD, combined with inequality in accessing surgical intervention, limited durability of prosthetic valves, and the procedural complications of valve replacement (e.g. infection, perivalvular regurgitation) all impose the need to uncover novel therapeutic targets to delay or even prevent the progression of VHD (Figure 1).

Figure 1:

Diagnostics, Imaging, Intervention, Biobanking, Bioengineering, Target Discovery and Preclinical and Clinical Development are major contemporary pillars contributing to a holistic understanding of multifactorial valvular heart disease.

Gaps in knowledge: Calcific aortic valve disease (CAVD)

The term calcific aortic valve disease (CAVD) rather than “degenerative” aortic stenosis is used broadly as it reflects the spectrum of sclerotic and fibrotic thickening and stiffening and eventual mineralization of valve tissue that is present across the various stages of this disease. Mineralization is primarily composed of dystrophic calcification, along with ~11% of ectopic, osteogenic production of bone-like matrix in the form of osseous metaplasia.^6–8 Once symptomatic and untreated, CAVD confers a dismal prognosis; the estimated 2-year mortality rate of severe aortic valve stenosis is approximately 50%.⁹

Alterations in molecular and cellular pathways can contribute to changes in valvular architecture and lead to malformations such as bicuspid aortic valve (BAV) instead of a prototypical tri-leaflet structure.¹⁰ Patients with BAV develop hemodynamically significant disease, need valve replacement decades earlier, and suffer from a cumulative lifetime morbidity burden of nearly 90%.¹¹

Calcification and mechanical stress are major contributors to CAVD; however, the underlying molecular mechanisms remain elusive. The current paradigm suggests that valvular interstitial cells (VICs) are a plastic cell population and can differentiate into activated myofibroblast-like cells contributing to collagen production, matrix remodeling, fibrosis and calcification during disease.¹² Emerging evidence also suggests that several developmental cellular lineages contribute to unique valvular structure and the underappreciated cellular heterogeneity of valvular leaflets,¹³ thus extending the old paradigm. Active biological mechanisms that alter the structure and function of the aortic valve can contribute simultaneously or independently to CAVD, including inflammation, oxidative stress, hyperphosphatemia, and hyperlipidemia. Indeed, genome-wide association studies (GWAS) of aortic valve calcification and stenosis have implicated lipoprotein(a), a major carrier of inflammatory oxidized phospholipids, as a genetic regulator of CAVD;¹⁴ early lipid-lowering therapy may delay the need for aortic valve replacement in hypercholesterolemic patients with asymptomatic mild aortic valve stenosis, but its applicability to cases of symptomatic stenosis remains unproven.¹⁵

Inflammation and immunity are largely underrecognized drivers of CAVD. During the early proinflammatory disease stage, activated macrophages and CD8-positive T lymphocytes drive disease progression through pathological matrix remodeling and release of osteogenic cytokines. Interleukin-6 and tumor necrosis factor-α can trigger osteogenic signaling via activation of bone morphogenic protein family members and Wnt signaling. Emerging evidence also suggests that VICs and macrophages can release calcifying extracellular vesicles.¹⁶ These vesicles serve as loci for nucleation of hydroxyapatite via complexing of Annexin 1, 5, S100A9, and/or tissue non-specific alkaline phosphatase. On the other hand, macrophages may contribute to the formation of valvular osteoclast-like cells, albeit dysfunctional due to their lack of calcium-resorptive potential. As macrophages can participate in both the deposition of mineral and its clearance, they are a uniquely attractive therapeutic target for CAVD.

Gaps in knowledge: Mitral valve disease

Mitral valve disease, if left untreated, can lead to serious life-threatening complications, including heart failure. There are a number of initiators/drivers of mitral pathophysiology, including ischemic regurgitation (structural ventricular remodeling due to coronary artery disease), degenerative, genetic (syndromic or non-syndromic), and rheumatic (damage resulting from post-infectious non-pyogenic immune activation caused by S. pyogenes). Echocardiography has defined the excessive valve motion in mitral valve prolapse, valve restriction by papillary muscle tethering in ischemic mitral regurgitation, and the central role of mitral apparatus abnormalities in causing left ventricle outflow tract obstruction in hypertrophic cardiomyopathy; thus setting the stage for surgical and transcatheter interventions.¹⁷ Orifice area dynamics and 3D imaging now guide individually tailored repairs, and imaging gauges rheumatic mitral stenosis suitability for balloon commissurotomy.

The heart increases mitral leaflet area and mechanical stretch to match the expanding left ventricle in aortic insufficiency; but this is counteracted by maladaptive fibrotic changes in the tethered valves of ischemic mitral regurgitation, mediated by endothelial-to-mesenchymal transition.¹⁸ Motivated by such clinical observations, studies have identified key cellular and molecular factors responsible for adaptive versus maladaptive profibrotic changes leading to VHD and heart failure. For instance, mitral valve endothelial cells were shown to be activated by transforming growth factor (TGF)-β1; inducing CD45 (protein tyrosine phosphatase) expression that in turn increased expression of collagen and multiple TGFβs.¹⁹ The potential to inhibit valve fibrosis in ischemic mitral regurgitation via pharmacological inhibition of CD45 was also demonstrated. Circulating factors activating serotonin receptors²⁰ and releasing molecular brakes on proliferative Wnt/β-catenin²¹ can also provide therapeutic clues.

The molecular histopathology of rheumatic heart disease further reveals the role of TGF-β and challenges the need to understand fibrosis-associated neovascularization. Novel biomarkers such as prothymosin-α provided insights into immune-triggered valve damage and its female predominance, thereby increasing hope for primary therapy.²²

In mitral valve prolapse, imaging translates population genetics to clinical outcomes in order to reveal altered ciliary mechano-sensing and disrupted planar cell polarity among other potential initiating and associated factors that can guide therapeutic prevention of VHD progression.²³ Molecular histopathology further differentiates diffuse myxomatous disease from more localized disruption in fibroelastic deficiency, while imaging valve strain can innovatively link basic and mechanical changes.²⁴

In future, interactions of valves with annular and ventricular structures provide opportunities to study the intersection of biomechanics and molecular changes through understanding how flattening the mitral annular saddle can augment leaflet stresses and worsen mitral valve prolapse;²⁵ how prolapse-induced forces can generate localized, proarrhythmic ventricular fibrosis;²⁶ and how local and global remodeling of the ischemic or myopathic ventricle can trigger intrinsic valve changes.

Gaps in knowledge: Bioprosthetic valves

The demand for cardiovascular devices is increasing as the incidence of cardiovascular diseases rises, the population ages, and medical technology advances. Implantation of bioprosthetic heart valves is increasingly becoming a treatment of choice in patients requiring heart valve replacement either via open-heart surgery or transcatheter valve replacement. On the other hand, mechanical valves continue to be associated with bleeding risk due to anticoagulation therapy. Both surgical and transcatheter replacement procedures use bioprosthetic valves that are currently manufactured from glutaraldehyde-fixed porcine valves or bovine pericardium. They are less thrombogenic and exhibit superior hemodynamic properties. However, bioprosthetic valves have a limited lifespan due to the lack of live resident cells capable of maintaining the tissue extracellular matrix, typically 7-8 years.²⁷ This structural valve degeneration (SVD) encompasses a gamut of bioprosthetic valve failure mechanisms including leaflet calcification, protein infiltration, inflammation and oxidative stress, protein glycation, thrombosis, and (micro)structural changes due to mechanical stress overload.²⁸ It is still unclear whether mechanisms of SVD could be mediated by calcium phosphate precipitation caused by abundance of cell debris that may serve as loci for nucleation, recipient cells provoking both humoral and cellular immune responses, production of human antibodies against α-Gal and NeuGc in bioprosthetic tissues, which may further enhance immune cell recruitment and associated calcification or other undiscovered yet mechanisms. Interestingly, young recipient age, hypertension, and metabolic syndrome are clinical risk factors for SVD, and may provide insight into specific failure mechanisms and potential mitigation strategies.²⁹ Indeed, given the rising demand for bioprosthetic valve implantation worldwide, new strategies to reduce immunogenicity of animal tissues used for their fabrication with adequate removal of residual antigens following decellularization are sorely needed.³⁰ While transcatheter valve replacement rates, which are governed by expanded approval into low- and medium-risk patients, the availability of novel devices, and the potential for repeat procedures (i.e. “valve-in-valve”), are on the rise, further understanding mechanisms of bioprosthetic valve failure is mandated. This method paves the way towards insertion of tissue-engineered heart valves that could potentially use off-the-shelf scaffolds to attract, house and instruct appropriate autologous cells, in what is termed “in situ regeneration”. Though clinical translation remains challenging and elusive, tissue engineering is a promising approach in replicating the sophisticated functions of a normal valve, including adaptation and growth, which could become a not-too-distant reality.

Future directions

The typical pipeline of drug discovery and development is slow, and translational success rates of new drug targets in clinical development are poor. To advance novel therapeutics to the bedside, the field must urgently apply innovative basic science approaches, such as multi-omics, systems biology, network medicine and artificial intelligence-based drug prediction (Figure 1).³¹ In addition, development of new disease models and new platforms to study and validate new targets are necessary.³² Emerging single-cell and multi-omics platforms have already identified novel and clinically-promising VHD drug targets, including monoamine oxidase,³³ major facilitator superfamily domain containing 5 (MFSD5),³⁴ and sortilin.³⁵ In particular, sortilin is a mechanistically-informative and diagnostically-useful cardiovascular calcification target and may be a potent biomarker, as it is associated with aortic calcification and cardiovascular risk in men independently from C-reactive protein and low-density lipoprotein (LDL) cholesterol. GWAS demonstrated an association of sortilin and MFSD5 with aortic stenosis in a large patient cohort,^33,34,36 thus substantiating these discoveries at the genomic level. With an increased availability of new drug targets coupled with the development of novel techniques of analyzing complex networks in order to prioritize drug targets for translation, clinical trials will continue to play a major role in validating future pharmacotherapies for multifactorial VHD diseases (Figure 2).

Figure 2:

Centennial milestones of surgical, (bio)engineering, and basic/clinical scientific research in the field of valvular heart disease.

A path forward: driving societal and governmental awareness towards interdisciplinary research

The current scourge of VHD requires a multidisciplinary approach to drastically improve our understanding of basic pathobiological mechanisms, combined with raising awareness within governments and populations of the global impact of valve diseases and future opportunities to prevent their progression.

Interdisciplinary studies, spanning imaged valve changes, clinical outcomes, basic findings in model systems, genetic variations, and circulating factors have ushered in a new era for potential prevention of valve disease progression and its adverse impact on myocardial contractility and electrical stability. Encouraging such collaborative research is an emerging international priority.³⁷