Evaluating Medical Therapy for Calcific Aortic Stenosis: JACC State-of-the-Art Review

Abstract

Despite numerous promising therapeutic targets, there are no proven medical treatments for calcific aortic stenosis (AS). Multiple stakeholders need to come together and several scientific, operational, and trial design challenges must be addressed to capitalize on the recent and emerging mechanistic insights into this prevalent heart valve disease. This review briefly discusses the pathobiology and most promising pharmacologic targets, screening, diagnosis and progression of AS, identification of subgroups that should be targeted in clinical trials, and the need to elicit the patient voice earlier rather than later in clinical trial design and implementation. Potential trial end points and tools for assessment and approaches to implementation and design of clinical trials are reviewed. The efficiencies and advantages offered by a clinical trial network and platform trial approach are highlighted. The objective is to provide practical guidance that will facilitate a series of trials to identify effective medical therapies for AS resulting in expansion of therapeutic options to complement mechanical solutions for late-stage disease.

Keywords: aortic valve stenosis; computed tomography; echocardiography; medical therapy; randomized clinical trial; trial endpoints; valvular heart disease.

Figure 1.. Disease Progression in Calcific Aortic Stenosis (CAS).

Panel A. Anatomical progression of CAS with valve anatomy viewed from the aortic side and open in systole. Panel B. Corresponding clinically relevant risk factors and histological development of CAS. Early lesion initiation by lipid infiltration into the subendothelium (LPA, FADS1/2). Infiltration initiation due to mechanical stress, dyslipidemia or abnormal valve morphology. Lp(a), LDL, OxLDL, and OxPLs enter into the subendothelial space triggering the recruitment, activation, and proliferation of monocytes and macrophages. At the molecular level, the calcification process driven by the oxidized phospholipid content of OxLDLs, leads to the enzymatic generation of LysoPA via ATX. In turn, LysoPA promotes osteogenic transition though the production of BMP2, which associates, with the expression of bone-related transcription factors like RUNX2 and MSX2. In addition, activation of macrophages in aortic valve by OxLDL promotes the production of TNFα and IL1β with pro-osteogenic properties. Chymase and ACE promote the production of angiotensin II, which increases the synthesis and secretion of collagen by VICs. This leads to an imbalance in metalloproteinase synthesis/inhibition pathway fibrous tissue begins to accumulate in the aortic valve. Early in the disease progression VICs and macrophages secret microvesicles initiating microcalcification. Overexpression of ENNP1 and ALP further increases osteogenic mineralization. Inset: Regulation of Notch1 transcription. H19 suppresses transcription of Notch1 by blocking the binding of p53 to the Notch1 promoter. The microRNA miR-34a is able to bind directly to the Notch1 transcript resulting in decreased translation of Notch1 mRNA. Both pathways of Notch1 suppression result in an increase CDH11 expression and calcification of the aortic valve. Panel C. Therapeutic modalities currently under investigation for CAS. ACE=angiotensin-converting enzyme; ALP=alkaline phosphatase; ATX=autotaxin; BMP2=bone morphogenetic protein 2; CAS=calcific aortic stenosis; CDH11=cadherin-11; ENNP1=ectonucleotidases; IL1β=Interleukin 1β; Lp(a)=lipoprotein(a); LDL=low-density lipoprotein; LysoPA=lysophosphatidic acid; MSX2=homeobox protein; NO-cGMP=nitric oxide cyclic guanosine monophosphate; OxLDL=oxidized LDL; OxPLs=oxidized phospholipids; RUNX2=runt-related transcription factor2; TNFα=tumor necrosis factor α; VIC=valve interstitial cell.

Figure 2.. Sample sizes for AS medical therapy trials by imaging modality.

Estimates are based upon the measurement error (noise) and the average progression observed for each imaging assessment (progression to noise or Cohens co-efficient). The number of participants required in a study to detect a given treatment effect size at different levels of power are plotted. For each modality an upper bound at 90% power and lower bound at 70% are plotted with α=0.05 for all. Nominal treatment effects up to 50% of the measured annualized progression for each modality are considered. Group size calculations should also consider the proportion of non- interpretable scans that may be encountered. AVA, aortic valve area; AV Vmax, maximum transvalvular velocity; CT-AVC, aortic valve calcification by computed tomography. (reproduced from Doris et al. Heart 2020 (83) Creative Commons Attribution 4.0 Unported (CC BY 4.0) license)

Figure 3.. Proposed AS Medical Therapy Trial Endpoints and Design.

A clinical trial network could facilitate the execution of a platform trial with endpoints, design, and data analysis characteristics as shown. AS, aortic stenosis; AVA, aortic valve area; CT-AVC, aortic valve calcification on computed tomography; V_peak, peak transvalvular velocity.

Central Illustration.. Over-arching Approach to Evaluate Medical Therapy for Calcific Aortic Stenosis.

Scientific advances in key areas combined with collaboration across multiple stakeholders (facilitated by the Heart Valve Collaboratory) could establish a clinical trial network purpose-fit to implement a platform trial to identify and validate effective and safe medical therapies for progressive aortic stenosis. AS, aortic stenosis; AVA, aortic valve area; AVC, aortic valve calcification; EMR, electronic medical record; FDA, Food and Drug Administration; NaF, sodium fluoride; NIH, National Institutes of Health.