PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction

Dalt, L. Da; Castiglioni, Laura; Baragetti, Andrea; Audano, Matteo; Svecla, M.; Bonacina, Fabrizia; Pedretti, Silvia; Uboldi, Patrizia; Benzoni, Patrizia; Giannetti, Federica; Barbuti, Andrea; Pellegatta, Fabio; Indino, Serena; Donetti, Elena; Sironi, Luigi; Mitro, Nico; Catapano, Alberico L.; Norata, Giuseppe Danilo

doi:10.1093/eurheartj/ehab431

Cited by 65 publications

(60 citation statements)

References 35 publications

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“…In our previous study, we demonstrated that adult ventricular cardiomyocytes constitutively express and secrete PCSK9 [ 12 , 26 ]. Moreover, secreted PCSK9 co-activates signal transduction pathways that depress cardiac function [ 14 , 26 ]. In line with these ex vivo studies, an inverse relationship between PCSK9 and cardiac function, quantified as left ventricular ejection fraction (LVEF), was shown [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

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Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Deletion but Not Inhibition of Extracellular PCSK9 Reduces Infarct Sizes Ex Vivo but Not In Vivo

Schreckenberg

Wolf

Szabados

et al. 2022

IJMS

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Hypoxia upregulates PCSK9 expression in the heart, and PCSK9 affects the function of myocytes. This study aimed to investigate the impact of PCSK9 on reperfusion injury in rats and mice fed normal or high-fat diets. Either the genetic knockout of PCSK9 (mice) or the antagonism of circulating PCSK9 via Pep2-8 (mice and rats) was used. Isolated perfused hearts were exposed to 45 min of ischemia followed by 120 min of reperfusion. In vivo, mice were fed normal or high-fat diets (2% cholesterol) for eight weeks prior to coronary artery occlusion (45 min of ischemia) and reperfusion (120 min). Ischemia/reperfusion upregulates PCSK9 expression (rats and mice) and releases it into the perfusate. The inhibition of extracellular PCSK9 does not affect infarct sizes or functional recovery. However, genetic deletion largely reduces infarct size and improves post-ischemic recovery in mice ex vivo but not in vivo. A high-fat diet reduced the survival rate during ischemia and reperfusion, but in a PCSK9-independent manner that was associated with increased plasma matrix metalloproteinase (MMP)9 activity. PCSK9 deletion, but not the inhibition of extracellular PCSK9, reduces infarct sizes in ex vivo hearts, but this effect is overridden in vivo by factors such as MMP9.

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Section: Discussionmentioning

confidence: 99%

“…The signaling of oxLDL involves LOX-1 (lectine-like oxidized low-density lipoprotein receptor-1) and dynamin-related protein 1 (Drp1), with the latter increasing mitochondria-induced oxidative stress [ 13 ]. Furthermore, PCSK9 deficiency may support heart failure [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Deletion but Not Inhibition of Extracellular PCSK9 Reduces Infarct Sizes Ex Vivo but Not In Vivo

Schreckenberg

Wolf

Szabados

et al. 2022

IJMS

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“…However, the relationship found in the present study could also be dependent on factors that still need to be investigated, given the complex interaction between lipid metabolism, PCSK9 and the heart [ 19 ]. Indeed, a recently published study on PCSK9 knock-out mice found that PCSK9 deficiency could negatively affect cardiac lipid metabolism (increased left ventricular thickness and an increased cardiac accumulation of lipid droplets were associated with a reduced density of mitochondrial cristae leading to impaired oxidative phosphorylation and mitochondrial metabolism) in a LDLR-independent manner, contributing to the development of HF and secondarily to high NPs levels [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Plasma Levels of Proprotein Convertase Subtilisin/Kexin Type 9 Are Inversely Associated with N-Terminal Pro B-Type Natriuretic Peptide in Older Men and Women

et al. 2022

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Background and Aims: Cardiac natriuretic peptides (NPs) exert several metabolic effects, including some on lipid metabolism. Higher NPs levels are likely to be associated with a favorable lipid profile. In in vitro studies, NPs have been found to modulate low-density lipoprotein receptor (LDLR) trafficking by preventing proprotein convertase subtilisin/kexin type 9 (PCSK9) overexpression. The aim of our study is to investigate a possible association between plasma levels of PCSK9 and N-terminal pro B-type natriuretic peptide (NT-proBNP) in vivo. Methods: We performed a cross-sectional study on 160 consecutive older male and female patients hospitalized for medical conditions. Patients taking lipid-lowering drugs and patients with an admission diagnosis of acute heart failure were excluded. Fasting blood samples were collected after clinical stabilization of the acute illness, the day before discharge. Results: The mean age was 87.8 ± 6.4 years with a female prevalence (62.5%). The median NT-proBNP was 2340 (814–5397) pg/mL. The mean plasma PCSK9 was 275.2 ± 113.2 ng/mL. We found an inverse correlation between plasma PCSK9 and NT-proBNP (r = −0.280; p = 0.001). This association was confirmed after taking into account NT-proBNP tertiles (plasma PCSK9 levels: 317.4 ± 123.6 ng/mL in the first tertile, 283.3 ± 101.8 ng/mL in the second tertile, 231.3 ± 99.0 ng/mL in the third tertile, p = 0.001) and even after an adjustment for confounding factors (beta = −0.361, p = 0.001 for ln(NT-proBNP); beta = −0.330, p = 0.001 for NT-proBNP tertiles). The strength of the correlation between plasma PCSK9 and NT-proBNP was likely greater in patients affected by type 2 diabetes mellitus (r = −0.483; p = 0.006) and in male patients (r = −0.431, p = 0.001). Conclusion: The inverse association found between PCSK9 and NT-proBNP plasma levels in our real-life clinical study supports the hypothesis that NPs may play a role in cholesterol metabolism, possibly through an inhibitory action on circulating PCSK9 concentrations, thus increasing the availability of LDLR.

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“…Interestingly, a recent study in mice showed that PCSK9 deficiency contributes to the development of HF with preserved ejection fraction. 21 …”

Section: Discussionmentioning

confidence: 99%

Alirocumab after acute coronary syndrome in patients with a history of heart failure

White

Schwartz

Szarek

et al. 2021

European Heart Journal

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Aims Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis, we evaluated outcomes in ODYSSEY OUTCOMES in patients with vs. without a history of HF randomized to the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo. Methods and results Among 18 924 patients with recent acute coronary syndrome (ACS) receiving intensive or maximum-tolerated statin treatment, the primary outcome of major adverse cardiovascular events (MACE) was compared in patients with or without a history of HF. The pre-specified secondary outcome of hospitalization for HF was also analysed. Overall, 2815 (14.9%) patients had a history of HF. Alirocumab reduced low-density lipoprotein cholesterol and lipoprotein(a) similarly in patients with or without HF. Overall, alirocumab reduced MACE compared with placebo [hazard ratio (HR): 0.85; 95% confidence interval (CI): 0.78–0.93; P = 0.0001]. This effect was observed among patients without a history of HF (HR: 0.78; 95% CI: 0.70–0.86; P < 0.0001), but not in those with a history of HF (HR: 1.17; 95% CI: 0.97–1.40; P = 0.10) (Pinteraction = 0.0001). Alirocumab did not reduce hospitalization for HF, overall or in patients with or without prior HF. Conclusion Alirocumab reduced MACE in patients without a history of HF but not in patients with a history of HF. Alirocumab did not reduce hospitalizations for HF in either group. Patients with a history of HF are a high-risk group that does not appear to benefit from PCSK9 inhibition after ACS. Key Question Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis of the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), we evaluated major adverse cardiovascular events (MACE) in patients with or without a history of HF assigned to treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo. Key Finding Alirocumab reduced low-density lipoprotein cholesterol similarly in patients with or without HF. However, alirocumab reduced MACE among patients without a history of HF, but not in those with a history of HF. Take Home Message The current hypothesis-generating analysis does not provide a basis to recommend PCSK9 inhibitors to patients with recent ACS and a history of HF. A prospective placebo-controlled evaluation of PCSK9 inhibition in this setting is warranted.

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PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction

Cited by 65 publications

References 35 publications

Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Deletion but Not Inhibition of Extracellular PCSK9 Reduces Infarct Sizes Ex Vivo but Not In Vivo

Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Deletion but Not Inhibition of Extracellular PCSK9 Reduces Infarct Sizes Ex Vivo but Not In Vivo

Plasma Levels of Proprotein Convertase Subtilisin/Kexin Type 9 Are Inversely Associated with N-Terminal Pro B-Type Natriuretic Peptide in Older Men and Women

Alirocumab after acute coronary syndrome in patients with a history of heart failure

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