Early experimental hypertension preserves the myocardial microvasculature but aggravates cardiac injury distal to chronic coronary artery obstruction.

Coronary artery disease is a leading cause of death. Hypertension (HT) increases the incidence of cardiac events, but its effect on cardiac adaptation to coexisting coronary artery stenosis (CAS) is unclear. We hypothesized that concurrent HT modulates microvascular function in chronic CAS and aggravates microvascular remodeling and myocardial injury. Four groups of pigs (n=6 each) were studied: normal, CAS, HT, and CAS+HT. CAS and HT were induced by placing local irritant coils in the left circumflex coronary artery and renal artery, respectively. Six weeks later multidetector computerized tomography (CT) was used to assess systolic and diastolic function, microvascular permeability, myocardial perfusion, and responses to adenosine in the "area at risk." Microvascular architecture, inflammation, and fibrosis were then explored in cardiac tissue. Basal myocardial perfusion was similarly decreased in CAS and CAS+HT, but its response to adenosine was significantly more attenuated in CAS. Microvascular permeability in CAS+HT was greater than in CAS and was accompanied by amplified myocardial inflammation, fibrosis, and microvascular remodeling, as well as cardiac systolic and diastolic dysfunction. On the other hand, compared with normal, micro-CT-derived microvascular (20-200 µm) transmural density decreased in CAS but not in HT or CAS+HT. We conclude that the coexistence of early renovascular HT exacerbated myocardial fibrosis and vascular remodeling distal to CAS. These changes were not mediated by loss of myocardial microvessels, which were relatively preserved, but possibly by exacerbated myocardial inflammation and fibrosis. HT modulates cardiac adaptive responses to CAS and bears cardiac functional consequences.

Analysis of machine perfusion benefits in kidney grafts: a preclinical study.

BACKGROUND: Machine perfusion (MP) has potential benefits for marginal organs such as from deceased from cardiac death donors (DCD). However, there is still no consensus on MP benefits. We aimed to determine machine perfusion benefits on kidney grafts. METHODS: We evaluated kidney grafts preserved in ViaspanUW or KPS solutions either by CS or MP, in a DCD pig model (60 min warm ischemia+24 h hypothermic preservation). Endpoints were: function recovery, quality of function during follow up (3 month), inflammation, fibrosis, animal survival. RESULTS: ViaspanUW-CS animals did not recover function, while in other groups early follow up showed similar values for kidney function. Alanine peptidase and ß-NAG activities in the urine were higher in CS than in MP groups. Oxydative stress was lower in KPS-MP animals. Histology was improved by MP over CS. Survival was 0% in ViaspanUW-CS and 60% in other groups. Chronic inflammation, epithelial-to-mesenchymal transition and fibrosis were lowest in KPS-MP, followed by KPS-CS and ViaspanUW-MP. CONCLUSIONS: With ViaspanUW, effects of MP are obvious as only MP kidney recovered function and allowed survival. With KPS, the benefits of MP over CS are not directly obvious in the early follow up period and only histological analysis, urinary tubular enzymes and red/ox status was discriminating. Chronic follow-up was more conclusive, with a clear superiority of MP over CS, independently of the solution used. KPS was proven superior to ViaspanUW in each preservation method in terms of function and outcome. In our pre-clinical animal model of DCD transplantation, MP offers critical benefits.

Enhanced endothelial progenitor cell angiogenic potency, present in early experimental renovascular hypertension, deteriorates with disease duration.

BACKGROUND: Endothelial progenitor cells (EPCs) augment neovascularization and repair of damaged tissues, but may undergo functional changes during exposure to cardiovascular risk factors. This study tested the hypothesis that early renovascular hypertension (RVH) modulates the temporal pattern of EPC function that deteriorates with disease duration. METHODS: RVH was induced in domestic pigs by unilateral renal artery stenosis. EPCs were cultured after 3, 6, and 12 weeks of RVH or normal control to evaluate EPC function, growth factor, and homing receptor expression. Plasma renin activity (PRA), vascular endothelial growth factor (VEGF), and its soluble receptor-1 (sFlt-1) were measured in plasma. EPCs (10 × 10) isolated from 3-week RVH or from normal pigs were also injected into control kidneys (n = 6-7, each group), and 4 weeks later single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were evaluated. Microvascular density was studied ex vivo using microcomputed tomography. RESULTS: Blood pressure peaked at 3 weeks and remained higher than normal throughout the study. Systemic PRA also peaked after 3 weeks of RVH and declined thereafter, whereas sFlt-1 showed a reciprocal pattern. In vivo, only RVH but not normal EPCs increased RBF, GFR, and microvascular density. RVH-EPCs showed in vitro enhanced proliferation, tube formation, VEGF, and homing receptor expression that peaked at 3 weeks, which were abolished by valsartan and returned to baseline levels after 12 weeks of RVH. EPC number remained unchanged throughout the study. CONCLUSION: A transient enhancement of EPC function, mediated by angiotensin II, may contribute to compensatory vascular adaptation in early RVH, but is lost as hypertension persists.

Reversal of experimental renovascular hypertension restores coronary microvascular function and architecture.

BACKGROUND: Hypertension (HTN) may lead to left ventricular hypertrophy and vascular dysfunction, which are independent factors for adverse cardiovascular outcomes. We hypothesized that decreased blood pressure by percutaneous transluminal renal angioplasty (PTRA) would improve the function and architecture of coronary microvessels, in association with decreased inflammation and fibrosis. METHODS: Three groups of pigs were studied: normal, HTN, and HTN+PTRA. After 6 weeks of renovascular HTN, induced by placing a local-irritant coil in the renal artery, pigs underwent PTRA or sham. Four weeks later multidetector-computed tomography (CT) was used to assess systolic, diastolic, and microvascular function, and responses to adenosine. Microvascular architecture, oxygen sensors, inflammation, and fibrosis were then explored in cardiac tissue. RESULTS: PTRA successfully decreased blood pressure and left ventricular hypertrophy. Basal fractional vascular volume (FVV) was similar among the groups, but its response to adenosine was significantly attenuated in HTN, whereas microvascular permeability (MP) and response to adenosine were greater than normal. Both were restored by PTRA. These were accompanied by increased myocardial expression of hypoxia-inducible factor (HIF)-1α, inflammation, and microvascular remodeling, including increased density of epicardial microvessels (20-200 µm), as well as cardiac diastolic dysfunction, all of which improved by reversal of HTN. However, PTRA only partially decreased myocardial fibrosis. CONCLUSIONS: Reversal of early renovascular HTN improved coronary microvascular function and architecture and reversed myocardial hypertrophy and diastolic dysfunction, in association with decreased levels of myocardial ischemia and inflammation markers, underscoring the benefits of blood pressure normalization for preservation of cardiovascular function and structure.