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. 2021 Feb 9;77(5):575-589.
doi: 10.1016/j.jacc.2020.11.059.

Local Pressure Drives Low-Density Lipoprotein Accumulation and Coronary Atherosclerosis in Hypertensive Minipigs

Rozh H Al-Mashhadi  1 , Ahmed L Al-Mashhadi  2 , Zahra P Nasr  3 , Martin Bødtker Mortensen  2 , Esmeralda A Lewis  4 , Emilio Camafeita  5 , Kristian Ravlo  3 , Zheer Al-Mashhadi  6 , Daniel W Kjær  7 , Johan Palmfeldt  3 , Peter Bie  8 , Jesper M Jensen  9 , Bjarne L Nørgaard  9 , Erling Falk  2 , Jesús Vázquez  5 , Jacob F Bentzon  10
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Free article

Local Pressure Drives Low-Density Lipoprotein Accumulation and Coronary Atherosclerosis in Hypertensive Minipigs

Rozh H Al-Mashhadi et al. J Am Coll Cardiol. .
Free article

Abstract

Background: The mechanisms by which hypertension accelerates coronary artery disease are poorly understood. Patients with hypertension often have confounding humoral changes, and to date, no experimental models have allowed analysis of the isolated effect of pressure on atherosclerosis in a setting that recapitulates the dimensions and biomechanics of human coronary arteries.

Objectives: This study sought to analyze the effect of pressure on coronary atherosclerosis and explore the underlying mechanisms.

Methods: Using inflatable suprarenal aortic cuffs, we increased mean arterial pressure by >30 mm Hg in the cephalad body part of wild-type and hypercholesterolemic proprotein convertase subtilisin kexin type 9 (PCSK9)D374Y Yucatan minipigs for >1 year. Caudal pressures remained normal.

Results: Under hypercholesterolemic conditions in PCSK9D374Y transgenic minipigs, cephalad hypertension accelerated coronary atherosclerosis to almost 5-fold with consistent development of fibroatheromas that were sufficiently large to cause stenosis on computed tomography angiography. This was caused by local pressure forces, because vascular beds shielded from hypertension, but exposed to the same humoral factors, showed no changes in lesion formation. The same experiment was conducted under normocholesterolemic conditions in wild-type minipigs to examine the underlying mechanisms. Hypertension produced clear changes in the arterial proteome with increased abundance of mechanical strength proteins and reduced levels of infiltrating plasma macromolecules. This was paralleled by increased smooth muscle cells and increased intimal accumulation of low-density lipoproteins in the coronary arteries.

Conclusions: Increased pressure per se facilitates coronary atherosclerosis. Our data indicate that restructuring of the artery to match increased tensile forces in hypertension alters the passage of macromolecules and leads to increased intimal accumulation of low-density lipoproteins.

Keywords: atherosclerosis; coronary artery disease; hypertension; low-density lipoproteins; minipigs; proteome.

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Conflict of interest statement

Funding Support And Author Disclosures This work was supported by grants from the Danish Heart Foundation Independent Research Funding Denmark and the Ministerio de Economia, Industria y Competividad with cofunding from the Fondo Europeo de Desarrollo Regional (SAF2016-75580-R and PGC2018-097019-B-I00), the Carlos III Institute of Health-Fondo de Investigación Sanitaria (IPT17/0019–ISCIII-SGEFI/ERDF, ProteoRed), the Fundació la Marató de TV3 (grant 122/C/2015) and “la Caixa” Banking Foundation (project code HR17-00247). The CNIC is supported by the Instituto de Salud Carlos III, the Ministerio de Ciencia e Innovación, and the Pro Centro Nacional de Investigaciones Cardiovasculares Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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