Crane, John A.

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. Conclusion— 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.

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.

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.

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.