Severe familial hypercholesterolemia impairs the regulation of coronary blood flow and oxygen supply during exercise

Abstract

Accelerated development of coronary atherosclerosis is a defining characteristic of familial hypercholesterolemia (FH). However, the recent data highlight a significant cardiovascular risk prior to the development of critical coronary stenosis. We, therefore, examined the hypothesis that FH produces coronary microvascular dysfunction and impairs coronary vascular control at rest and during exercise in a swine model of FH. Coronary vascular responses to drug infusions and exercise were examined in chronically instrumented control and FH swine. FH swine exhibited ~tenfold elevation of plasma cholesterol and diffuse coronary atherosclerosis (20-60 % plaque burden). Similar to our recent findings in the systemic vasculature in FH swine, coronary smooth muscle nitric oxide sensitivity was increased in vivo and in vitro with maintained endothelium-dependent vasodilation in vivo in FH. At rest and during exercise, FH swine exhibited increased myocardial O2 extraction resulting in reduced coronary venous SO2 and PO2 versus control. During exercise in FH swine, the transmural distribution of coronary blood flow was unchanged; however, a shift toward anaerobic cardiac metabolism was revealed by increased coronary arteriovenous H(+) concentration gradient. This shift was associated with a worsening of cardiac efficiency (relationship between cardiac work and O2 consumption) in FH during exercise owing, in part, to a generalized reduction in stroke volume which was associated with increased left atrial pressure in FH. Our data highlight a critical role for coronary microvascular dysfunction as a contributor to impaired myocardial O2 balance, cardiac ischemia, and impaired cardiac function prior to the development of critical coronary stenosis in FH.

Long-term spironolactone treatment reduces coronary TRPC expression, vasoconstriction, and atherosclerosis in metabolic syndrome pigs

“…However, subsequent clinical studies revealed controversial findings, indicating that spironolactone may or may not affect total cholesterol level in human subjects [ 9 , 17 , 39 , 48 ]. Elevated levels of plasma cholesterol are strongly associated with atherosclerosis development [ 4 ]. Therefore, we investigated spironolactone’s effect on total plasma cholesterol level in the Ossabaw pig model.…”

Perturbations in myocardial perfusion and oxygen balance in swine with multiple risk factors: a novel model of ischemia and no obstructive coronary artery disease

“…For example, we previously showed that CMD was already present in swine 2.5 months after the induction of DM and HC in the absence of coronary atherosclerosis [63]. Furthermore, CMD remained present in swine with 15-month diabetes and hypercholesterolemia with modest non-obstructive atherosclerosis [57], and was also found in a swine model of familial hypercholesterolemia (FH) with moderate (20-60%) coronary plaque burden [5]. Here, we observed coronary microvascular endothelial dysfunction in isolated small arteries studied ex vivo, in the absence of atherosclerosis which is in line with our previous study [54].…”

“…The presence of risk factors, including DM, HC and CKD, has been associated with CMD and INOCA in both experimental [5,57,63] and clinical [2,41,42,44] studies. For example, we previously showed that CMD was already present in swine 2.5 months after the induction of DM and HC in the absence of coronary atherosclerosis [63].…”

Endurance exercise training does not limit coronary atherosclerosis in familial hypercholesterolemic swine

“…; Bender et al. , ). We have found that this protocol yields greater consistency in the development of coronary atherosclerosis than with the standard pig chow.…”

“…The total segment was subdivided into three equal sections (10 mm each) and total vessel volume, lumen volume, total plaque volume, and percent plaque burden were determined in the proximal, mid, and distal segments as previous (Bender et al. ), that is, vessel volume = EEL area x length; lumen volume = lumen area x length; total plaque burden volume = (EEL area‐lumen area) x length; and percent plaque burden = total plaque volume/vessel volume.…”