Introduction
Summary of the pathophysiology of CAVD
CAVD and ASCVD, two sides of the same coin?
CAVD, a chronic inflammatory disease
Local valvular inflammation
Valvular endothelial damage
Valvular interstitial cells contribute to valvular inflammation
Macrophages
Oxidized lipids: central regulators of inflammation in CAVD
Beyond the valve: systemic inflammation and circulating immune cell activation
Monocyte activation in CAVD
Neutrophils: important players in CAVD?
Proposed new mechanisms for circulating immune cell activation in CAVD
Trained immunity
Clonal haematopoiesis and CAVD
Imaging of valvular inflammation and calcification
Pharmacological treatment to prevent severe CAVD
Trial | Patients | Study design | Intervention | Primary + echocardiographic outcomes | Inflammatory outcome | Refs. |
---|---|---|---|---|---|---|
SALTIRE | 155 patients with CAVD and aortic jet velocity ≥ 2.5 m/s | Double-blind, placebo-controlled RCT FU: 25 months (median, range 7–36) | Atorvastatin 80 mg per day versus placebo | - Aortic jet velocity change/year Atorvastatin: 0.199 ± 0.210 m/s Placebo:0.203 ± 0.208 m/s (P = 0.95) - Calcification progression/year Atorvastatin: 22.3 ± 21.0% Placebo: 21.7 ± 19.8% (P = 0.93) | None mentioned | [30] |
TASS | 47 patients with asymptomatic CAVD with mean systolic gradient ≥ 15 mmHg and peak velocity ≥ 2.0 m/s | Placebo-controlled RCT FU: 2.3 ± 1.2 years (median, SD) | Atorvastatin 20 mg per day versus placebo | - HR 0.78 (95% CI 0.32–1.87; P = 0.569) for MACE - CAVD progression: Mean gradient at last FU (mmHg): Atorvastatin: 31.3 ± 12.3 Placebo: 29.9 ± 14.8 (P = NS) Aortic valve calcification at last FU (Agatston score): Atorvastatin: 2979 ± 1228 Placebo: 2749 ± 1376 (P = NS) | CRP level (mg/dl) 0.14 ± 0.66 in atorvastatin group versus 0.33 ± 1.39 in control group (P < 0.05) after 12 month FU. P = NS after 24 months FU | [32] |
SEAS | 1873 patients with mild to moderate, asymptomatic CAVD | Multicentre, double-blind, placebo-controlled RCT FU: 52.2 months (median) | Simvastatin 40 mg + ezetimibe 10 mg per day versus placebo | - HR 0.96 (95% CI 0.83 to 1.12; P = 0.59) for MACE - Increase in peak velocity (m/s): Simvastatin + ezetimibe: 0.61 ± 0.59 Placebo: 0.62 ± 0.61 (P = 0.83) - Increase mean gradient (mmHg/year): Simvastatin + ezetimibe: 2.7 ± 0.1 Placebo: 2.8 ± 0.1 - Decrease in AVA (cm2/year): − 0.03 ± 0.01 in both groups | None mentioned | [126] |
ASTRON-OMER | 269 patients with mild or moderate CAVD | Multicentre, double-blind, placebo-controlled RCT FU: 3.5 years (median, IQR 2.1–4.5) | Rosuvastatin 40 mg per day versus placebo | - Annualized peak AS gradient increase (mmHg): Rosuvastatin: 6.3 ± 6.9 Placebo: 6.1 ± 8.2 (P = 0.83) - Increase in mean gradient (mmHg): Rosuvastatin: 10.7 Placebo: 9.6 (P = 0.49) - Decrease in AVA (cm2): Rosuvastatin: − 0.19 Placebo: − 0.16 (P = 0.79) | CRP reduction of 0.33 mg/L in rosuvastatin group compared to an increase of 0.095 mg/L in the placebo group (P = 0.002) | [23] |
FOURIER (post hoc analysis) | 27,564 patients with stable atherosclerotic disease receiving statin therapy | Multicentre, double-blind, placebo-controlled RCT FU: 26 months (median, IQR 22–30) | Subc. evolocumab injection (140 mg biweekly or 420 mg monthly) versus placebo | - Post hoc analysis: HR 0.48 (95% CI, 0.25–0.93) for overall CAVD events after first year of evolocumab | None mentioned | [15] |
Lipid-lowering therapy
Trial | Patients | Study design | Intervention | Primary outcome | Clinicaltrials. gov identifier | Refs. |
---|---|---|---|---|---|---|
PCSK9 inhibitors in the progression of aortic stenosis | 140 patients with mild to moderate CAVD | Phase 2 multicentre randomized, double-blind, placebo-controlled clinical trial Follow-up 2 years | Subcutaneous injection of EPC biweekly versus placebo | Calcium score progression measured by cardiac CT (Agatston score) and by NaF PET–CT | NCT03051360 | [157] |
EAVaLL | 238 patients with aortic sclerosis or mild CAVD and elevated Lp(a) | Phase 2, randomized, placebo-controlled clinical trial Follow-up 2 years | Niacin 1500–2000 mg versus placebo | Calcium score progression measured by cardiac CT | NCT02109614 | [158] |
Lp(a) HORIZON | 7680 patients with established CVD and elevated Lp(a) | Phase 3 multicentre, randomized, double-blind, placebo-controlled clinical trial Follow-up 4 years | Subcutaneous injection of TQQJ230 80 mg monthly versus placebo | Time to first occurrence of MACE | NCT04023552 | [160] |