Experimental coronary artery stenosis accelerates kidney damage in renovascular hypertensive swine.

The impact of coronary artery stenosis (CAS) on renal injury is unknown. Here we tested whether the existence of CAS, regardless of concurrent atherosclerosis, would induce kidney injury and magnify its susceptibility to damage from coexisting hypertension (HT). Pigs (seven each) were assigned to sham, left-circumflex CAS, renovascular HT, and CAS plus HT groups. Cardiac and nonstenotic kidney functions, circulating and renal inflammatory and oxidative markers, and renal and microvascular remodeling were assessed 10 weeks later. Myocardial perfusion declined distal to CAS. Systemic levels of PGF2-α isoprostane, a marker of oxidative stress, increased in CAS and CAS plus HT, whereas single-kidney blood flow responses to acetylcholine were significantly blunted only in CAS plus HT compared with sham, HT, and CAS, indicating renovascular endothelial dysfunction. Tissue expression of inflammatory and oxidative markers were elevated in the CAS pig kidney, and further magnified in CAS plus HT, whereas angiogenic factor expression was decreased. Bendavia, a mitochondria-targeted peptide, decreased oxidative stress and improved renal function and structure in CAS. Furthermore, CAS and HT synergistically amplified glomerulosclerosis and renal fibrosis. Thus, mild myocardial ischemia, independent of systemic atherosclerosis, induced renal injury, possibly mediated by increased oxidative stress. Superimposed HT aggravates renal inflammation and endothelial dysfunction caused by CAS, and synergistically promotes kidney fibrosis, providing impetus to preserve cardiac integrity in order to protect the kidney.

Valsartan regulates myocardial autophagy and mitochondrial turnover in experimental hypertension.

Renovascular hypertension alters cardiac structure and function. Autophagy is activated during left ventricular hypertrophy and linked to adverse cardiac function. The angiotensin II receptor blocker, valsartan, lowers blood pressure and is cardioprotective, but whether it modulates autophagy in the myocardium is unclear. We hypothesized that valsartan would alleviate autophagy and improve left ventricular myocardial mitochondrial turnover in swine renovascular hypertension. Domestic pigs were randomized to control, unilateral renovascular hypertension, and renovascular hypertension treated with valsartan (320 mg/d) or conventional triple therapy (reserpine+hydralazine+hydrochlorothiazide) for 4 weeks after 6 weeks of renovascular hypertension (n=7 each group). Left ventricular remodeling, function, and myocardial oxygenation and microcirculation were assessed by multidetector computer tomography, blood oxygen level-dependent MRI, and microcomputer tomography. Myocardial autophagy, markers for mitochondrial degradation and biogenesis, and mitochondrial respiratory-chain proteins were examined ex vivo. Renovascular hypertension induced left ventricular hypertrophy and myocardial hypoxia, enhanced cellular autophagy and mitochondrial degradation, and suppressed mitochondrial biogenesis. Valsartan and triple therapy similarly decreased blood pressure, but valsartan solely alleviated left ventricular hypertrophy, ameliorated myocardial autophagy and mitophagy, and increased mitochondrial biogenesis. In contrast, triple therapy only slightly attenuated autophagy and preserved mitochondrial proteins, but elicited no improvement in mitophagy. These data suggest a novel potential role of valsartan in modulating myocardial autophagy and mitochondrial turnover in renovascular hypertension-induced hypertensive heart disease, which may possibly bolster cardiac repair via a blood pressure-independent manner.

Mitochondrial targeted peptides attenuate residual myocardial damage after reversal of experimental renovascular hypertension.

BACKGROUND: Renovascular hypertension (RVHT) increases cardiovascular morbidity and mortality. Renal revascularization with percutaneous transluminal renal angioplasty and stenting (PTRS) may reverse RVHT but may not fully regress cardiac remodeling and damage, possibly due to persistent myocardial insults. Bendavia is a mitochondrial targeted peptide that reduces ischemic cardiomyopathy by improving mitochondrial function. However, its potential for attenuating residual myocardial damage after reversal of RVHT has not been explored. We hypothesized that treatment with Bendavia as an adjunct to PTRS would improve cardiac function and oxygenation, and decrease myocardial injury in swine RVHT. METHODS AND RESULTS: After 6 weeks of RVHT (unilateral renal artery stenosis) or control, pigs underwent PTRS (or sham), with adjunct continuous infusion of Bendavia (0.05  mg/kg intravenously, 30  min before to 3.5  h after PTRS) or vehicle (n = 7 each). Four weeks later, systolic and diastolic function were assessed by multidetector computed tomography, myocardial oxygenation by blood oxygen level-dependent MRI, and myocardial morphology, apoptosis, mitochondrial biogenesis, and fibrosis evaluated ex vivo. PTRS restored blood pressure in both groups, yet E/A ratio remained decreased. Myocardial oxygenation and mitochondrial biogenesis improved, and myocardial inflammation, oxidative stress, and fibrosis normalized in association with improvement in diastolic function in RVHT + PTRS + Bendavia animals. CONCLUSION: Adjunct Bendavia during PTRS in swine RVHT improved diastolic function and oxygenation and reversed myocardial tissue damage. This approach may allow a novel strategy for preservation of cardiac function and structure in RVHT.

Evolution of cardiac and renal impairment detected by high-field cardiovascular magnetic resonance in mice with renal artery stenosis.

BACKGROUND: Renal artery stenosis (RAS) promotes hypertension and cardiac dysfunction. The 2-kidney, 1-clip mouse model in many ways resembles RAS in humans and is amenable for genetic manipulation, but difficult to evaluate noninvasively. We hypothesized that cardiovascular magnetic resonance (CMR) is capable of detecting progressive cardiac and renal dysfunction in mice with RAS and monitoring the progression of the disease longitudinally. METHODS: RAS was induced at baseline in eighteen mice by constricting the renal artery. Nine additional animals served as normal controls. CMR scans (16.4 T) were performed in all mice one week before and 2 and 4 weeks after baseline. Renal volumes and hemodynamics were assessed using 3D fast imaging with steady-state precession and arterial spin labelling, and cardiac function using CMR cine. Renal hypoxia was investigated using blood oxygen-level dependent (BOLD) MR. RESULTS: Two weeks after surgery, mean arterial pressure was elevated in RAS mice. The stenotic kidney (STK) showed atrophy, while the contra-lateral kidney (CLK) showed hypertrophy. Renal blood flow (RBF) and cortical oxygenation level declined in the STK but remained unchanged in CLK. Moreover, cardiac end-diastolic and stroke volumes decreased and myocardial mass increased. At 4 weeks, STK RBF remained declined and the STK cortex and medulla showed development of hypoxia. Additionally, BOLD detected a mild hypoxia in CLK cortex. Cardiac end-diastolic and stroke volumes remained reduced and left ventricular hypertrophy worsened. Left ventricular filling velocities (E/A) indicated progression of cardiac dysfunction towards restrictive filling. CONCLUSIONS: CMR detected longitudinal progression of cardiac and renal dysfunction in 2K, 1C mice. These observations support the use of high-field CMR to obtain useful information regarding chronic cardiac and renal dysfunction in small animals.

Obesity-metabolic derangement preserves hemodynamics but promotes intrarenal adiposity and macrophage infiltration in swine renovascular disease.

Obesity-metabolic disorders (ObM) often accompany renal artery stenosis (RAS). We hypothesized that the coexistence of ObM and RAS magnifies inflammation and microvascular remodeling in the stenotic kidney (STK) and aggravates renal scarring. Twenty-eight obesity-prone Ossabaw pigs were studied after 16 wk of a high-fat/high-fructose diet or standard chow including ObM-sham, ObM-RAS, Lean-RAS, or Lean-sham (normal control) groups. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed by multidetector computed tomography (CT), renal oxygenation and tubular transport capability by blood-oxygen-level-dependent MRI, and microcirculation by micro-CT for vessel density, and Western blotting for protein expressions of angiogenic factors (VEGF/FLK-1). Renal vein and inferior vena cava levels of inflammatory cytokines were measured to evaluate systemic and kidney inflammation. Macrophage (MØ) infiltration and subpopulations, fat deposition in the kidney, and inflammation in perirenal and abdominal fat were also examined. GFR and RBF were decreased in Lean-STK but relatively preserved in ObM-STK. However, ObM-STK showed impaired tubular transport function, suppressed microcirculation, and stimulated glomerulosclerosis. ObM diet interacted with RAS to blunt angiogenesis in the STK, facilitated the release of inflammatory cytokines, and led to greater oxidative stress than Lean-STK. The ObM diet also induced fat deposition in the kidney and infiltration of proinflammatory M1-MØ, as also in perirenal and abdominal fat. Coexistence of ObM and RAS amplifies renal inflammation, aggravates microvascular remodeling, and accelerates glomerulosclerosis. Increased adiposity and MØ-accentuated inflammation induced by an ObM diet may contribute to structural injury in the post-STK kidney.

Angiotensin receptor blockade has protective effects on the poststenotic porcine kidney.

Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ARBs) may induce an acute decrease of glomerular filtration rate (GFR) in the stenotic kidney in renal artery stenosis, but most patients tolerate these drugs well. We hypothesized that angiotensin-converting enzyme inhibitors/ARBs stabilize stenotic kidney function during prolonged treatment by conferring protective effects. We tested this in control domestic pigs and pigs with renal artery stenosis untreated or treated with Valsartan, or triple therapy (seven pigs in each group) for 4 weeks starting 6 weeks after stenosis induction. Renal function, oxygenation, tubular function, and microcirculation were assessed by multi-detector computed tomography (CT), blood oxygen level-dependent magnetic-resonance imaging, and micro-CT. Valsartan and triple therapy decreased blood pressure similarly; however, Valsartan did not change the GFR of the stenotic kidney compared with renal artery stenosis and was similar to triple therapy. Both Valsartan and triple therapy stimulated microvascular density and improved tubular function. Valsartan also caused a greater increase of angiogenic factors and a decrease in oxidative stress, which were related to higher cortical perfusion and tubular response than triple therapy. Thus, Valsartan did not decrease stenotic kidney GFR, but improved cortical perfusion and microcirculation. These beneficial effects may partly offset the hemodynamic GFR reduction in renal artery stenosis and preserve kidney function.

Hemodynamic determinants of perivascular collateral development in swine renal artery stenosis.

BACKGROUND: Renal artery stenosis (RAS) resulting in reduced renal blood flow (RBF) is a common cause of secondary hypertension and deterioration of renal function, which may lead to end-stage renal disease. Recruitment and formation of periarterial collateral vessels may serve to bypass RAS and restore distal blood supply. We hypothesized that development of collaterals around RAS may preserve kidney function. METHODS: Collateral formation index (CI) was assessed using multidetector computed tomography as fractional vascular volume surrounding the stenosis in 31 pigs with unilateral RAS. Single kidney RBF and glomerular filtration rate (GFR) were also measured. RESULTS: Of 25 pigs that developed significant stenosis (≥65%), 8 demonstrated minor collateral development (CI < 0.3), and 17 showed major collateral development (CI ≥ 0.3). The degree of RAS was significantly higher in pigs with major collaterals compared with pigs with minor collaterals, and poststenotic kidney cortical volume, perfusion, RBF, and GFR were significantly lower. In a subset of pigs matched for the degree of RAS, RBF and GFR remained lower in pigs with major collaterals. CONCLUSIONS: We conclude that collaterals develop in animals with significant RAS in proportion to its severity and might be triggered by distal injury, such as decreases in cortical volume and perfusion. However, development of collaterals was unable to confer measurable benefits for stenotic kidney function distal to severe RAS.

Magnetic resonance elastography noninvasively detects in vivo renal medullary fibrosis secondary to swine renal artery stenosis.

OBJECTIVES: Magnetic resonance elastography (MRE) can noninvasively sample tissue stiffness in vivo. Renal fibrosis secondary to renal artery stenosis (RAS), which is aggravated in atherosclerotic RAS (ARAS), may increase its stiffness. An increase in cortical stiffness in vivo can be masked by intrinsic hemodynamic determinants, whereas renal medullary stiffness is less dependent on renal hemodynamics. Therefore, this study tested the hypothesis that MRE-determined medullary stiffness would correspond to the histological degree of medullary fibrosis in stenotic kidneys in RAS and detect its exacerbation in ARAS. MATERIALS AND METHODS: Seventeen pigs were studied 10 weeks after induction of unilateral RAS (n = 6), ARAS (n = 5), or sham (n = 6). Stiffness of the cortex and the medulla was determined through 3-dimensional MRE, and renal perfusion and function were determined using multidetector computed tomography. Kidney fibrosis was subsequently assessed ex vivo using the Masson trichrome staining. RESULTS: Renal stenotic cortex and medulla were significantly more fibrotic in RAS and ARAS compared with healthy kidney. However, MRE detected increased stiffness in RAS compared with the healthy kidney (12.7 ± 0.41 kPa vs 10.7 ± 0.18 kPa; P = 0.004) only in the medulla, which was further increased in ARAS (16.6 ± 1.3 kPa; P = 0.017 vs RAS). Magnetic resonance elastography-derived medullary, but not cortical, stiffness significantly correlated with histological degree of fibrosis, although cortical and medullary fibroses were correlated. Renal blood flow and function were similarly decreased in RAS and ARAS compared with the healthy kidney. CONCLUSIONS: Noninvasive 3-dimensional MRE detects increased renal medullary stiffness in RAS and ARAS in vivo, which correlates with its fibrosis ex vivo and may also reflect cortical fibrosis. Hence, MRE-derived medullary stiffness can be potentially useful in detecting renal fibrosis and track disease progression.

Polycystic kidneys have decreased vascular density: a micro-CT study.

OBJECTIVE: Polycystic kidney disease (PKD) is a common cause of end-stage renal failure and many of these patients suffer vascular dysfunction and hypertension. It remains unclear whether PKD is associated with abnormal microvascular structure. Thus, this study examined the renovascular structure in PKD. METHODS: PKD rats (PCK model) and controls were studied at 10 weeks of age, and mean arterial pressure (MAP), renal blood flow, and creatinine clearance were measured. Microvascular architecture and cyst number and volume were assessed using micro-computed tomography, and angiogenic pathways evaluated. RESULTS: Compared with controls, PKD animals had an increase in MAP (126.4 ± 4.0 vs. 126.2 ± 2.7 mmHg) and decreased clearance of creatinine (0.39 ± 0.09 vs. 0.30 ± 0.05 mL/min), associated with a decrease in microvascular density, both in the cortex (256 ± 22 vs. 136 ± 20 vessels per cm2) and medullar (114 ± 14 vs. 50 ± 9 vessels/cm2) and an increase in the average diameter of glomeruli (104.14 ± 2.94 vs. 125.76 ± 9.06 mm). PKD animals had increased fibrosis (2.2 ± 0.2 fold vs. control) and a decrease in the cortical expression in hypoxia inducible factor 1-α and vascular endothelial growth factor. CONCLUSIONS: PKD animals have impaired renal vascular architecture, which can have significant functional consequences. The PKD microvasculature could represent a therapeutic target to decrease the impact of this disease.

Changes in glomerular filtration rate after renal revascularization correlate with microvascular hemodynamics and inflammation in Swine renal artery stenosis.

BACKGROUND: The selection of patients with renal artery stenosis (RAS) likely to improve glomerular filtration rate (GFR) after percutaneous transluminal renal angioplasty is difficult. We examined basal hemodynamic and inflammatory factors linked to improved stenotic kidney (STK) function after percutaneous transluminal renal angioplasty in swine RAS. METHODS AND RESULTS: Fifteen pigs after 6 weeks of hemodynamically significant RAS were studied before and 4 weeks after technically successful percutaneous transluminal renal angioplasty+stenting. STK and contralateral kidney hemodynamics and function were evaluated by multidetector computed-tomography before and after acetylcholine challenge. Single-kidney deoxyhemoglobin (R2*, reciprocal to blood relaxation) and energy-dependent tubular function were assessed using blood-oxygen-level-dependent magnetic resonance imaging before and after furosemide. Baseline renal vein and inferior vena cava levels of inflammatory markers were measured and their gradient and net release calculated. Baseline parameters were compared with normal (n=7) and sham-RAS (n=7) pigs and correlated with the change in STK-GFR after revascularization (ΔGFR). Four weeks after percutaneous transluminal, renal angioplasty blood pressure was normalized in all animals, but STK-GFR improved in 10 of 15 (ΔGFR =+22.0±8.5 mL/min). ΔGFR correlated inversely with basal STK-GFR, renal release of inflammatory markers, and medullary R2* response to furosemide, but directly with GFR response to acetylcholine. Basal contralateral kidney GFR correlated directly with ΔGFR. CONCLUSIONS: Low basal STK-GFR with preserved response to acetylcholine may predict benefit from revascularization in RAS, whereas renal inflammation and robust STK-R2* responses to furosemide (possibly reflecting avid tubular oxygen consumption) are associated with less favorable outcomes. These tools may be useful for identification of patients likely to improve renal function after revascularization.

Humanin prevents intra-renal microvascular remodeling and inflammation in hypercholesterolemic ApoE deficient mice.

AIMS: Humanin (HN) is an endogenous mitochondrial-derived cytoprotective peptide that has shown protective effects against atherosclerosis and is expressed in human vessels. However, its effects on the progression of kidney disease are unknown. We hypothesized that HN would protect the kidney in the early phase of atherogenesis. MAIN METHODS: Forty-eight mice were studied in four groups (n=12 each). Twenty-four ApoE deficient mice were fed a 16-week high-cholesterol diet supplemented with saline or HN (4mg/kg/day, intraperitoneal). C57BL/6 mice were fed a normal diet supplemented with saline or HN. Microvascular architecture was assessed with micro-CT and vascular wall remodeling by alpha-SMA staining. The effects of HN on angiogenesis, inflammation, apoptosis and fibrosis were evaluated in the kidney tissue by Western blotting and histology. KEY FINDINGS: Cortical microvascular spatial density and media/lumen area ratio were significantly increased in high-cholesterol diet fed ApoE deficient mice, but restored by HN. HN up-regulated the renal expressions of anti-angiogenic proteins angiostatin and TSP-1, and inhibited angiopoietin-1. HN attenuated inflammation by down-regulating MCP-1, TNF-alpha and osteopontin. HN also tended to restore pSTAT3 and attenuated Bax expression, suggesting blunted apoptosis. Kidney collagen IV expression was alleviated by HN treatment. SIGNIFICANCE: HN attenuates renal microvascular remodeling, inflammation and apoptosis in the early stage of kidney disease in hypercholesterolemic ApoE(-/-) mice. HN may serve as a novel therapeutic target to mitigate kidney damage in early atherosclerosis.

Transition from obesity to metabolic syndrome is associated with altered myocardial autophagy and apoptosis.

OBJECTIVE: Transition from obesity to metabolic-syndrome (MetS) promotes cardiovascular diseases, but the underlying cardiac pathophysiological mechanisms are incompletely understood. We tested the hypothesis that development of insulin resistance and MetS is associated with impaired myocardial cellular turnover. METHODS AND RESULTS: MetS-prone Ossabaw pigs were randomized to 10 weeks of standard chow (lean) or to 10 (obese) or 14 (MetS) weeks of atherogenic diet (n=6 each). Cardiac structure, function, and myocardial oxygenation were assessed by multidetector computed-tomography and Blood Oxygen Level-Dependent-MRI, the microcirculation with microcomputed-tomography, and injury mechanisms by immunoblotting and histology. Both obese and MetS showed obesity and dyslipidemia, whereas only MetS showed insulin resistance. Cardiac output and myocardial perfusion increased only in MetS, yet Blood Oxygen Level-Dependent-MRI showed hypoxia. Inflammation, oxidative stress, mitochondrial dysfunction, and fibrosis also increased in both obese and MetS, but more pronouncedly in MetS. Furthermore, autophagy in MetS was decreased and accompanied by marked apoptosis. CONCLUSIONS: Development of insulin resistance characterizing a transition from obesity to MetS is associated with progressive changes of myocardial autophagy, apoptosis, inflammation, mitochondrial dysfunction, and fibrosis. Restoring myocardial cellular turnover may represent a novel therapeutic target for preserving myocardial structure and function in obesity and MetS.

Compartmental analysis of renal BOLD MRI data: introduction and validation.

OBJECTIVES: Functional blood oxygenation level-dependent (BOLD) magnetic resonance imaging is a powerful tool to assess renal function, but BOLD analysis using T2* image differentiation of cortex and medulla is laborious and prone to errors. We developed and validated an alternative compartmental analysis method to differentiate renal cortical and medullary BOLD relaxivity index, R2*. This method uses whole-kidney regions of interest (ROI), thus eliminating the need for anatomic cortical and medullary definition. MATERIALS AND METHODS: Nine hypertensive patients and 11 domestic pigs, some with renal artery stenosis, were studied using BOLD MRI before and after injection of furosemide, which reduces medullary oxygen consumption. R2* in cortex and medulla estimated before and after furosemide with the compartmental method were compared with those obtained using conventional T2* image selection for ROI (manual ROI method), and a reference method with ROIs obtained using contrast-enhanced computerized tomography images were coregistered for the same kidneys. RESULTS: All 3 methods provided similar cortical R2* values, but the Bland-Altman methods' agreement confidence intervals of the reference and compartmental-derived medullary R2* response in humans and pigs were smaller than those in the manual ROI method. Operator dependency in swine was lower in the compartmental method, and its estimates of variation were almost 1/3 compared with the manual ROI method. CONCLUSIONS: The new compartmental method, which is less labor intensive than the conventional method, provides comparable and less variable kidney R2* estimations, especially in renal medulla. This method could be useful for analysis of kidney BOLD data.

Blood oxygen level-dependent magnetic resonance imaging identifies cortical hypoxia in severe renovascular disease.

Atherosclerotic renal artery stenosis has a range of manifestations depending on the severity of vascular occlusion. The aim of this study was to examine whether exceeding the limits of adaptation to reduced blood flow ultimately leads to tissue hypoxia, as determined by blood oxygen level dependent MRI. We compared 3 groups of hypertensive patients, 24 with essential hypertension, 13 with "moderate" (Doppler velocities 200-384 cm/s), and 17 with "severe" atherosclerotic renal artery stenosis (ARAS; velocities >384 cm/s and loss of functional renal tissue). Cortical and medullary blood flows and volumes were determined by multidetector computed tomography. Poststenotic kidney size and blood flow were reduced with ARAS, and tissue perfusion fell in the most severe lesions. Tissue medullary deoxyhemoglobin, as reflected by R2* values, was higher as compared with the cortex for all of the groups and did not differ between subjects with renal artery lesions and essential hypertension. By contrast, cortical R2* levels were elevated for severe ARAS (21.6±9.4 per second) as compared with either essential hypertension (17.8±2.3 per second; P<0.01) or moderate ARAS (15.7±2.1 per second; P<0.01). Changes in medullary R2* after furosemide administration tended to be blunted in severe ARAS as compared with unaffected (contralateral) kidneys. These results demonstrate that severe vascular occlusion overwhelms the capacity of the kidney to adapt to reduced blood flow, manifest as overt cortical hypoxia as measured by blood oxygen level-dependent MRI. The level of cortical hypoxia is out of proportion to the medulla and may provide a marker to identify irreversible parenchymal injury.

Noninvasive In vivo assessment of renal tissue elasticity during graded renal ischemia using MR elastography.

OBJECTIVES: : Magnetic resonance elastography (MRE) allows noninvasive assessment of tissue stiffness in vivo. Renal arterial stenosis (RAS), a narrowing of the renal artery, promotes irreversible tissue fibrosis that threatens kidney viability and may elevate tissue stiffness. However, kidney stiffness may also be affected by hemodynamic factors. This study tested the hypothesis that renal blood flow (RBF) is an important determinant of renal stiffness as measured by MRE. MATERIAL AND METHODS: : In 6 anesthetized pigs MRE studies were performed to determine cortical and medullary elasticity during acute graded decreases in RBF (by 20%, 40%, 60%, 80%, and 100% of baseline) achieved by a vascular occluder. Three sham-operated swine served as time control. Additional pigs were studied with MRE 6 weeks after induction of chronic unilateral RAS (n = 6) or control (n = 3). Kidney fibrosis was subsequently evaluated histologically by trichrome staining. RESULTS: : During acute RAS the stenotic cortex stiffness decreased (from 7.4 ± 0.3 to 4.8 ± 0.6 kPa, P = 0.02 vs. baseline) as RBF decreased. Furthermore, in pigs with chronic RAS (80% ± 5.4% stenosis) in which RBF was decreased by 60% ± 14% compared with controls, cortical stiffness was not significantly different from normal (7.4 ± 0.3 vs. 7.6 ± 0.3 kPa, P = 0.3), despite histologic evidence of renal tissue fibrosis. CONCLUSION: : Hemodynamic variables modulate kidney stiffness measured by MRE and may mask the presence of fibrosis. These results suggest that kidney turgor should be considered during interpretation of elasticity assessments.

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.

Early atherosclerosis aggravates the effect of renal artery stenosis on the swine kidney.

Atherosclerotic renal artery stenosis (ARAS) is increasingly identified in patients with end-stage renal disease. Renal function in ARAS patients deteriorates more frequently than in nonatherosclerotic renal artery stenosis (RAS). This study was designed to test the hypothesis that atherosclerosis modifies the relationship between single-kidney hemodynamics and function and the severity of stenosis. The degree of unilateral RAS in domestic pigs (4 normal, 26 RAS, and 22 ARAS) was correlated with renal function and hemodynamics evaluated by 64-slice multidetector computerized tomography before and after endothelium-dependent challenge with ACh. The degree of stenosis and increase in mean arterial pressure were similar in RAS and ARAS. Stenotic single-kidney volume, blood flow, glomerular filtration rate, and cortical perfusion were lower than normal in both RAS and ARAS, but only in RAS correlated inversely with increasing degree of stenosis (r = -0.62, r = -0.49, r = -0.51, and r = -0.46, respectively, P < 0.05 for all). Basal tubular fluid concentration capacity and stenotic cortical perfusion response to ACh were both blunted only in ARAS. This study shows that atherosclerosis modulates the impact of a stenosis in the renal artery on stenotic kidney hemodynamics, function, and tubular dynamics. These observations underscore the direct intrarenal effect of atherogenic factors on the kidneys.