Intramyocardial Arteries Research Articles

Elastolytic Cathepsin Induction/Activation System Exists in Myocardium and Is Upregulated in Hypertensive Heart Failure

Cathepsins are cysteine proteases that participate in various types of tissue remodeling. However, their expressions during myocardial remodeling have not been examined. In this study, we investigated their expressions in the left ventricular (LV) myocardium of rats and humans with hypertension-induced LV hypertrophy or heart failure (HF). Real-time PCR and immunoblot analysis revealed that the abundance of cathepsin S mRNA or protein in the LV tissues was greater in rats or humans with HF than in those with hypertrophy or in control subjects. Immunostaining showed that cathepsin S was localized predominantly to cardiac myocytes and coronary vascular smooth muscle cells, but also overlapped in part with macrophages. Elastic lamina fragmentations significantly increased in the LV intramyocardial coronary arteries of HF rats. The amount of elastolytic activity in the extract of the LV myocardium was markedly increased for HF rats compared with controls, and this activity was mostly because of cathepsin S. Although the amount of elastin mRNA was increased in the LV myocardium of HF rats, the area of interstitial elastin was not. The expression of interleukin 1beta was increased in the LV myocardium of HF rats, and this cytokine was found to increase the expression and activity of cathepsin S in cultured neonatal cardiomyocytes. These results suggest that cathepsin S participates in pathological LV remodeling associated with hypertension-induced HF. This protease is, thus, a potential target for therapeutics aimed at preventing or reversing cardiac remodeling.

Effect of Maternal Protein Restriction in Rats on Cardiac Fibrosis and Capillarization in Adulthood

This study examines the effect of maternal protein restriction in rats on levels of cardiac fibrosis, myocardial capillarization, and media:lumen ratio of intramyocardial arteries in adult offspring. Female Wistar Kyoto rats were fed either a normal protein diet (NPD; 20% casein) or a low-protein diet (LPD; 8.7% casein) during pregnancy and lactation. Female offspring (seven per group) were weaned at 4 wk of age and grown to adulthood. At 24 wk of age, the offspring were perfusion fixed. Cardiac fibrosis and media:lumen ratio of intramyocardial arterioles was assessed using image analysis and cardiac capillarization was stereologically investigated. Body weights at 2 and 24 wk of age were significantly reduced (31% and 8%, respectively) in the LPD offspring; however, heart size was not different at 24 wk. Importantly by adulthood, there was a significant 15% increase in left ventricular interstitial fibrosis in LPD offspring. There were no differences in levels of perivascular fibrosis, myocardial capillarization, or in the media:lumen ratio of intramyocardial arteries between groups. Because cardiac fibrosis is associated with impaired cardiac contractility and arrhythmia, our results suggest that induction of interstitial fibrosis may contribute to the increased cardiac disease in adult subjects who were exposed to an adverse intrauterine environment.

Eplerenone offsets cardiac and aortic adverse remodeling in spontaneously hypertensive rats

Background Several studies have shown beneficial effects of eplerenone in hypertension and left ventricular dysfunction, but its action on cardiac and vascular changes secondary to blood pressure elevation are not clear yet. Methods Twenty-five male spontaneously hypertensive rats (SHR) were assigned into five groups: young SHR (16 weeks), control SHR (22 weeks), and SHR treated by eplerenone (50 mg/kg/day), enalapril (10 mg/kg/day) or eplerenone + enalapril during 6 weeks. Five Wistar male rats were used as reference group. Cardiac structure and aorta were analyzed by stereology and image analysis. Results The raise of blood pressure (202 ± 3 mm Hg in control SHR) was significantly attenuated by eplerenone (169 ± 2 mm Hg) or enalapril (170 ± 2 mm Hg, P < 0.001 versus control SHR), and more intensely by combined therapy (160 ± 2 mm Hg, P < 0.01 versus eplerenone or enalapril). The number of cardiomyocytes in left ventricle was preserved in enalapril group (35,660 ± 910 versus 16,220 ± 730 × 10 3 in control SHR, P < 0.01) but more significantly in eplerenone, alone or combined, groups (38,380 ± 439 and 38,660 ± 374 × 10 3, respectively, P < 0.001 versus control). The increased connective tissue volume density (35.8 ± 1.2%) noted in the left ventricle of control SHR was significantly attenuated by eplerenone (7.4 ± 0.8%), enalapril (8.0 ± 0.6%) or eplerenone + enalapril (6.0 ± 1.1%, P < 0.01 treated versus control SHR). Media-to-lumen ratio of intramyocardial arteries was reduced by enalapril, but more significantly by eplerenone alone or combined with enalapril. The increase of media cross-sectional area of aorta in control SHR was attenuated by eplerenone and/or enalapril. Conclusions Eplerenone is effective in attenuating cardiovascular remodeling in SHR, confirming the important role of aldosterone in this process.

Relation Between Flow Reserve Capacity of Penetrating Intramyocardial Coronary Arteries and Myocardial Fibrosis in Hypertension: Study Using Transthoracic Doppler Echocardiography

The purpose of this study was to compare coronary flow reserve (CFR) capacity of penetrating intramyocardial coronary artery (PICA) using transthoracic Doppler echocardiography and biochemical marker of myocardial fibrosis in hypertension (HTN). In 58 patients (male:female ratio = 31:27; mean age 47 +/- 9 years) with chest pain and normal coronary angiogram findings, the width of color Doppler signal and peak diastolic velocity of PICA flow were measured in the myocardium just beneath the apical impulse window using transthoracic Doppler echocardiography. PICA-CFR and PICA-width ratio were calculated as the ratio of hyperemic to baseline peak diastolic velocity and as the ratio of hyperemic to baseline width after the adenosine infusion (140 mug/kg/min), respectively. Serum carboxy-terminal propeptide of procollagen type I, as a biochemical marker, was measured and patients were divided into 3 groups: 19 with HTN and PICA-CFR less than 2.0 (group A); 23 with HTN and PICA-CFR of 2.0 or more (group B); and 16 who were normotensive with PICA-CFR of 2.0 or more (group C). Baseline peak diastolic velocity for group A was higher than the other two groups (P < .005 vs groups B and C). PICA-width ratio was higher than the other two groups (P < .005 vs groups B and C). Serum propeptide of type I was 137.1 +/- 16.6 ng/mL in group A, 96.2 +/- 13.7 ng/mL in group B, and 78.8 +/- 11.2 ng/mL in group C (P < .0001 vs group B and group C). PICA-CFR was closely related to serum propeptide of type I (P < .001, r = -0.723). The impaired PICA-CFR is related to myocardial fibrosis in patients with HTN, chest pain, and normal coronary angiogram results.

Off-Pump Coronary Revascularization: Operative Technique

Off-pump coronary artery bypass grafting can be performed in most patients undergoing surgical myocardial revascularization. The selection of patients for off-pump surgery is dependent on the surgeon’s knowledge and comfort with the techniques of off-pump revascularization. Early in a surgeon’s experience with off-pump revascularization, it is best to select patients with normal left ventricular size and function, relatively large epicardial coronary arteries free of diffuse calcific atherosclerosis, and coronary artery disease limited to the left anterior descending and right coronary artery systems. As the surgeon gains experience and confidence with off-pump techniques, patients with decreased left ventricular function, enlarged hearts, and coronary artery disease of the circumflex system may be performed off-pump. When the surgeon has mastered the techniques of off-pump coronary surgery, nearly all patients presenting for coronary revascularization may be considered, including those with severe left main coronary artery stenosis, poor left ventricular function, and intramyocardial coronary arteries. Relative contraindications to off-pump myocardial revascularization include patients with severely enlarged and dysfunctional hearts, mitral insufficiency, or small and diffusely diseased coronary arteries. Patients with hemodynamic instability and those with chest anatomy that prevents rightward displacement of the heart, such as pectus excavatum or previous left pneumonectomy, should not be selected for off-pump revascularization. Similar to on-pump coronary artery bypass grafting, off-pump myocardial revascularization is a complex operation composed of many steps. The operative steps of off-pump coronary artery revascularization are (1) incision and conduit preparation; (2) patient positioning; (3) target vessel exposure; (4) target vessel stabilization; (5) target vessel hemostasis and ischemia prevention; (6) construction of anastomoses; and (7) closure. Off-pump myocardial revascularization has the potential benefit of lowering the risk of coronary surgery by eliminating cardiopulmonary bypass and ascending aortic manipulation. The use of in situ and composite arterial grafts for coronary revascularization avoids the need for ascending aorta manipulation to construct proximal anastomoses. In this article, the techniques used in off-pump, multivessel coronary artery bypass grafting with in situ and composite arterial grafts is illustrated. Using these techniques of coronary artery exposure and stabilization, off-pump coronary revascularization can be performed safely and accurately in the majority of patients presenting for surgical revascularization. Whether off-pump revascularization lowers the risk of surgical revascularization has been a highly debated and controversial issue in coronary surgery during the last decade. Off-pump revascularization has the potential for lowering the risk of coronary surgery by eliminating cardiopulmonary bypass, and all arterial off-pump revascularization using in situ and composite grafts has the potential to further reduce risk by eliminating the need for aortic manipulation.

Exercise training attenuates cardiovascular adverse remodeling in adult ovariectomized spontaneously hypertensive rats

To study the combined effects of ovariectomy and regular exercise training on hypertension and on cardiac and aortic remodeling in spontaneously hypertensive rats (SHR). Three-month-old female spontaneously hypertensive rats (SHR) were ovariectomized (ovx) or were left intact (int) and divided in four groups (n = 7): sedentary (sed-ovx), exercise-trained (ex-ovx), sedentary intact (sed-int), and exercise-trained intact (ex-int). The exercise protocol was performed on a motor treadmill for 13 weeks. Blood pressure (BP), left ventricular myocardium and aortic wall were studied by light microscopy and stereology. Exercise-trained SHR showed a BP reduction of more than 15% compared with the matched sedentary SHR (sed-int: 210 +/- 5 mm Hg, sed-ovx: 225 +/- 4 mm Hg, ex-int: 178 +/- 2 mm Hg, ex-ovx: 180 +/- 3 mm Hg, P < 0.001). Ovariectomy caused adverse cardiac and aortic wall remodeling, including cardiomyocyte hypertrophy, myocardial interstitial reparative fibrosis and vascularization impairment with loss of cardiomyocytes, and aortic tunica media hypertrophy. Exercise training showed beneficial effects, mainly reduced BP, decreased cardiac hypertrophy due to hypertension, and increased myocardial vascularization. Ovariectomy accelerated cardiomyocyte loss in SHR while exercise training offset this process. Exercise training was the main factor influencing the improvement of intramyocardial arteries length density and significantly reduced the aortic wall thickness and increased the density of smooth muscle cell nuclei per tunica media unit area. In ovariectomized SHR, exercise training exerts beneficial effects diminishing adverse cardiac and aortic wall remodeling, mainly by reducing interstitial myocardial fibrosis, improving myocardial vascularization, and sustaining the number of cardiomyocytes.

961 Flow reserve capacity of penetrating intramyocardial coronary arteries and myocardial fibrosis in hypertensives

961 Flow reserve capacity of penetrating intramyocardial coronary arteries and myocardial fibrosis in hypertensives

Marsupialization of Intramyocardial Left Anterior Descending Artery: A Novel Approach for Easy Access During Revascularization

The left anterior descending (LAD) artery is the most important vessel bypassed during coronary revascularization procedures. This artery usually runs a superficial course, making it easy for localization and grafting. However, many times it takes a course deep in the myocardium or is embedded in thick epicardial fat, which results in technical challenges to the surgeon for localization and grafting. So far, many techniques are described for overcoming these problems, but all require cardiopulmonary bypass (CPB), and in fact, intramyocardial LAD is considered a relative contraindication for off-pump coronary artery bypass grafting (OPCAB). In the present era of enhanced interest in OPCAB, these techniques are not as helpful as they are for conventional CABG with CPB. Here, we describe a novel approach of marsupialization of the LAD for revascularization of intramyocardial LAD that is useful for off-pump as well as conventional revascularization procedures and makes grafting simple and reproducible.

Functional hierarchy of coronary circulation: direct evidence of a structure-function relation

The heart muscle is nourished by a complex system of blood vessels that make up the coronary circulation. Here we show that the design of the coronary circulation has a functional hierarchy. A full anatomic model of the coronary arterial tree, containing millions of blood vessels down to the capillary vessels, was simulated based on previously measured porcine morphometric data. A network analysis of blood flow through every vessel segment was carried out based on the laws of fluid mechanics and appropriate boundary conditions. Our results show an abrupt change in cross-sectional area that demarcates the transition from epicardial (EPCA) to intramyocardial (IMCA) coronary arteries. Furthermore, a similar pattern of blood flow was observed with a corresponding transition from EPCA to IMCA. These results suggest functional differences between the two types of vessels. An additional abrupt change occurs in the IMCA in relation to flow velocity. The velocity is fairly uniform proximal to these vessels but drops significantly distal to those vessels toward the capillary branches. This finding suggests functional differences between large and small IMCA. Collectively, these observations suggest a novel functional hierarchy of the coronary vascular tree and provide direct evidence of a structure-function relation.

Myocardial Contrast Echocardiography Assessment of Acute Changes in Collateral Perfusion of Contralateral Coronary Artery with Coronary Flow Reserve After Coronary Angioplasty

Coronary flow velocity reserve (CFVR) is used to evaluate the severity of epicardial and intramyocardial coronary artery disease. Collateral flow to an adjacent compromised myocardial territory may influence the CFVR of a specific artery. To assess the impact of collateral flow on CFVR, we measured CFVR and assessed perfusion area (PA) with myocardial contrast echocardiography in the right coronary arteries of 18 patients with total/subtotal occlusion of the left anterior descending coronary artery before and after angioplasty. A total of 10 patients had well-developed collaterals emerging from the right coronary artery (group I) and 8 patients did not (group II). Using a Doppler-tipped guidewire, we measured CFVR, which is defined as the ratio of papaverine-induced hyperemic average peak velocity of coronary flow to baseline. Before angioplasty of the left anterior descending coronary artery, CFVR was significantly reduced in group I compared with group II (2.35 +/- 0.47 vs 3.26 +/- 0.54, P < .01). Baseline average peak velocity in group I before angioplasty was significantly greater than that after angioplasty (23.7 +/- 11.6 vs 19.2 +/- 9.7 cm/s, P < .05). After angioplasty, CFVR immediately increased in group I to 3.46 +/- 0.54 ( P < .001). The increase in CFVR was well correlated with the decrement in PA after angioplasty (r = 0.883, P < .001). The CFVR of an artery that supplies extensive collaterals is limited because of an elevation in the baseline resting flow velocity. This restriction in CFVR improves proportionally with decreases in PA that occurs after angioplasty of the ipsilateral coronary artery. These data suggest that PA, in addition to coronary artery structure, influences CFVR.

Increased αCGRP potency and CGRP‐receptor antagonist affinity in isolated hypoxic porcine intramyocardial arteries

1. This study describes the effects of hypoxia on relaxing responses and cAMP production induced by the known vasodilator peptides: alphaCGRP, amylin (AMY) and adrenomedullin (AM) on isolated pig coronary arteries in vitro. 2. Hypoxic incubation increased the vasorelaxant effect of alphaCGRP (four-fold; P<0.05), AMY (3.2-fold; P<0.05), but not significantly for AM (two-fold; NS). 3. Whereas hypoxia had no effect on arterial cAMP levels, it significantly potentiated the production of cAMP stimulated of alphaCGRP and AMY, but not of AM. 4. The antagonist alphaCGRP(8-37) also exerted an increased effect in hypoxia. The Schild plot-derived pK(B) values revealed an increase in the apparent affinity of the antagonist for the CGRP(1) receptor from 7.0 to 7.2 under control conditions versus 8.0 in hypoxia. 5. Removal of endothelium, peptidase inhibitors, preincubation with the adenosine A(2A) receptor antagonist CSC (10(-3) M), the ATP-sensitive K-channel inhibitor glibenclamide (10(-5) M), the cyclooxygenase inhibitor indomethacin (10(-3) M) or NG-monomethyl-L-arginine (10(-4) M) had no effect on the alphaCGRP-induced vasorelaxation in hypoxia; neither did hypoxia influence the levels of CGRP and AM receptor mRNA. 6. We conclude that hypoxic incubation increases the relaxation and cAMP production induced by alphaCGRP and AMY in rings of porcine coronary arteries in vitro. A concomitant release of adenosine, a cyclooxygenase product, an endothelium-derived substance, activation of vascular ATP-sensitive K-channels, peptidase inhibitors or changes in CGRP and AM receptor mRNA cannot account for the changes observed in hypoxia. Moreover, alphaCGRP(8-37) showed increased affinity at the CGRP(1) receptor during hypoxia, possibly due to a conformational change at the CGRP(1) receptor site.

Frontiers in Cardiovascular Magnetic Resonance

Cardiovascular magnetic resonance (MR) is emerging as a multipurpose imaging modality for the assessment of cardiovascular disease in general and ischemic heart disease in particular. Currently, the pace of innovation is rapid, and the modality is changing from one that is used primarily as a research tool to one that is increasingly used in routine clinical practice. The process of innovation includes not only improvements in scanner hardware, such as coil and gradient technology, and the development of new contrast agents but also the development of novel pulse sequences. The concept of the pulse sequence, in which programming changes at the scanner can lead to fundamental changes in activating tissue, is unique to MR and gives this modality the potential to assess a vast number of biological parameters. Cardiovascular MR promises to play an important clinical and investigational role in both vascular and cardiac systems. Current and potential future applications of cardiovascular MR will be discussed with a particular focus on ischemic heart disease. Multidetector-row computed tomography, another promising and complementary noninvasive imaging technology, will be discussed briefly in relation to cardiovascular MR for the assessment of atherothrombotic disease. ### Nomenclature and Evolving Imaging Assessment Atherothrombosis is a systemic or multiterritory arterial disease that primarily affects the large- and medium systemic arteries, including the aorta and the carotid, coronary, and peripheral arteries. Although the epicardial coronary arteries appear to be the most susceptible to atherothrombosis,1,2 intramyocardial arteries are relatively resistant. The concept of multiterritory atherothrombosis has been addressed in 2 large studies of symptomatic patients that showed that at entry into the studies, 3% to 8% had symptomatic atherothrombotic disease in all 3 main arterial districts and 23% to 32% had disease in 2 districts.3,4 From a structural point of view, the 4 main components of the atherothrombotic plaques are as follows: (1) fibrocellular, …

Overweight is gender-dependent in prenatal protein–calorie restricted adult rats acting on the blood pressure and the adverse cardiac remodeling

Postnatal heart remodeling was studied in rats submitted to prenatal protein–calorie restriction (R). Offspring were divided in four groups: control male (CM) and female (CF) vs. restricted male (RM) and female (RF) and lived 120 days. The offspring blood pressure (BP) and biometry were periodically analyzed. In the euthanasia day, the left ventricular (LV) mass index, the cardiomyocyte nuclei profile number ( N[cmn]) (disector method), the cross-sectional cardiomyocyte area ( A[cm]) and the stereology for intramyocardial arteries (ima) were estimated. Interactions between gender and prenatal nutritional conditions were tested with the two-way ANOVA. RM animals showed higher BP and greater body mass and smaller LV mass index than the other groups. N[cmn] and stereology parameters of ima were smaller, and A[cm] was greater in the R groups rats than in the C groups rats; these structural changes were only dependent of the prenatal nutritional condition but not gender-dependent. In conclusion: hypertension and body and cardiac growth were influenced by the interaction between gender and prenatal nutritional conditions, while cardiac remodeling seems to be only programmed by the adverse intrauterine environment.

Reduced coronary flow reserve in Anderson-Fabry disease measured by transthoracic Doppler echocardiography

Coronary flow reserve was assessed in a patient with Anderson-Fabry disease complicated by symmetric left ventricular hypertrophy. Coronary flow reserve was measurable in all three major coronary arteries providing an opportunity to compare regional coronary flow reserve from different vascular beds. In this patient all the three vascular beds supplied diffusely hypertrophied myocardium. Coronary flow disturbances in small intramyocardial perforating arteries were visible. The coronary flow reserve was reduced to a similar level (around to 2.0) in all three major arteries. In our patient with Anderson-Fabry disease, the coronary vasodilatation was blunted in a diffuse pattern corresponding to the myocardial hypertrophy distribution. In small intramyocardial arteries coronary flow was also disturbed. Accordingly, retrograde systolic flow and accelerated anterograde diastolic flow were documented.

Beneficial effect of simvastatin and pravastatin treatment on adverse cardiac remodelling and glomeruli loss in spontaneously hypertensive rats

The aim of the present study was to investigate the possibility of different effects of the hydrophobic statin simvastatin and the hydrophilic statin pravastatin on the remodelling process in the overloaded left ventricle and renal cortex of SHRs (spontaneously hypertensive rats). Fifteen SHRs were treated for 40 days with simvastatin, pravastatin or placebo (water) via orogastric administration. Left ventricle and renal cortex were examined by light microscopy and stereology. LV (left ventricular) cardiomyocyte nuclei (N[cmn]) and glomeruli (N[gl]) numbers were estimated by the dissector method. BP (blood pressure) and serum triacylglycerols (triglycerides) were lower in the statin-treated groups than in the untreated control group. The volume density of the interstitial connective tissue was smaller and length density of the intramyocardial arteries, as well as the arteries/cardiomyocyte ratio, was greater in the statin-treated groups than in the control group. No difference was observed between the two statin-treated groups. The cross-sectional cardiomyocyte area was significantly smaller in the simvastatin-treated group than in the control or pravastatin-treated groups, and it was smaller in the pravastatin-treated group than in the control group. N[cmn] and N[gl] were greater in the two statin-treated groups than in the control group, but no significant difference was observed between the two statin-treated groups. In conclusion, administration of the statins simvastatin and pravastatin to SHRs effectively prevented the elevation in BP and serum triaclyglycerols, and also attenuated adverse cardiac and kidney remodelling by preventing LV hypertrophy, enhancing myocardial vascularization with the decrease in interstitial fibrosis and attenuating cardiomyocyte and glomerular loss.

The impaired flow reserve capacity of penetrating intramyocardial coronary arteries in apical hypertrophic cardiomyopathy

Coronary flow reserve (CFR) capacity of penetrating intramyocardial coronary artery (PICA) in apical hypertrophic (AH) cardiomyopathy has not been studied yet. We studied 65 patients with normal coronary angiogram results (mean age 56 +/- 10 years; 33 men, 32 women). Of these, 30 were normotensive without any left ventricular hypertrophy (control group), 24 had hypertension (HTN) without any left ventricular hypertrophy (HTN group), and 11 had AH cardiomyopathy (AH group). PICA-CFR and PICA-width ratio were calculated after the intravenous infusion of adenosine (140 microg/kg/min) just beneath the apical impulse window at a depth of 3 to 5 cm by using high-frequency transthoracic Doppler echocardiography. PICA-CFR was successfully measured in 59 (90.8%) of 65 patients. PICA-CFR was 1.65 +/- 0.49 in AH group, 2.50 +/- 0.77 in HTN group, and 2.42 +/- 0.73 in control group ( P < .005 vs HTN and control). PICA-width ratio was 1.45 +/- 0.42 in AH group, 2.14 +/- 0.72 in HTN group, and 1.81 +/- 0.55 in control group ( P = .025 vs HTN and control). PICA-CFR was closely related to width-ratio of PICA ( r = 0.448, P = .002). Conclusion PICA in AH has higher resting diastolic velocity, wider diameter, and impaired CFR compared with nonhypertrophied myocardium.

Expression, localisation and function of ACE and chymase in normal and atherosclerotic human coronary arteries

The expression, localisation and function of enzymes responsible for the local formation of angiotensin II in atherosclerotic and non-atherosclerotic human coronary arteries were studied. Human epicardial coronary arteries expressed mRNA for both ACE and chymase. Immunohistochemical studies revealed that ACE was localised to the vascular endothelium, and to a lesser extent the medial smooth muscle cells, in both large and small arteries. Chymase was detected in both types of vessel but was shown to be associated with mast cells. The contractions to angiotensin I in large arteries were inhibited only by a combination of quinaprilat and soyabean trypsin inhibitor. In the intramyocardial arteries the response to angiotensin I was markedly inhibited in the presence of chymostatin. These findings demonstrate that a dual pathway for the synthesis of angiotensin II is active in diseased and non-diseased coronary arteries.

Angiotensin II Type 1 Receptor Antagonist and Angiotensin-Converting Enzyme Inhibitor Altered the Activation of Cu/Zn-Containing Superoxide Dismutase in the Heart of Stroke-Prone Spontaneously Hypertensive Rats

Although angiotensin II type 1 (AT1) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors are known to reduce both reactive oxygen species (ROS) generated by activated NAD(P)H oxidase and vascular remodeling in hypertension, the effects of AT1 receptor antagonists or ACE inhibitors on ROS-scavenging enzymes remain unclear. We hypothesized that AT1 receptor antagonists or ACE inhibitors may modulate vascular remodeling via superoxide dismutase (SOD) in hypertension. Male stroke-prone spontaneously hypertensive rats (SHRSP) were treated for 6 weeks with a vehicle, an AT1 receptor antagonist (E4177; 30 mg/kg/day), or an ACE inhibitor (cilazapril; 10 mg/kg/day). We evaluated protein expression using immunoblots, determined SOD activities with a spectrophotometric assay, and measured NAD(P)H oxidase activity by a luminescence assay. The two drugs showed equipotent effects on blood pressure, left ventricular hypertrophy and fibrosis, and endothelial NO synthase in the SHRSP hearts. The wall-to-lumen ratio of the intramyocardial arteries and the NAD(P)H oxidase essential subunit p22(phox) and its activity were significantly reduced, whereas Cu/Zu-containing SOD (Cu/ZnSOD) expression and activity were significantly increased in the SHRSP hearts. Furthermore, E4177 reduced vascular remodeling more than did cilazapril not only by reducing p22(phox) expression and NAD(P)H oxidase activity but also by upregulating the Cu/ ZnSOD expression and its activity in the SHRSP hearts. Thus, both the AT1 receptor antagonist and the ACE inhibitor inhibited vascular remodeling and reduced ROS in SHRSP via not only a reduction in NAD(P)H oxidase but also an upregulation of Cu/ZnSOD.

Inhibition of Graft Coronary Arteriosclerosis after Heart Transplantation

Graft coronary arteriosclerosis (GCA) is the leading cause of long-term mortality after heart transplantation (HTx). The goal of this study was to demonstrate that inhibition of immunemediated injury by cyclosporine (CsA) protects the allograft from GCA. ACI-to-Lewis rat allografts were disparate in major and nonmajor histocompatibility loci. Isografts (Lewis-Lewis) were controls. Treatment groups received either olive oil or CsA at 2.5, 5, 10, or 20 mg/kg/day for 3 months. Histology (elastin) and immunohistochemistry using monoclonal antibodies to CD4, CD8, CD45R, RT1B, CD11b/c, CD25, and alpha-actin was performed to examine the epicardial and intramyocardial coronary arteries. Computerized image morphometry was utilized to measure intimal and medial thickness and area. Rats receiving olive oil or CsA at 2.5 mg/kg/day had severe rejection and no graft survival. CsA at 5 mg/kg/day resulted in less severe rejection with significant intimal and medial proliferation (P < 0.001). CsA at 10-20 mg/kg/day paralleled Lewis-Lewis isograft outcomes and inhibited arteriosclerotic vascular changes in the allograft (P < 0.001). Perivascular T-helper cells and macrophages were a characteristic finding with low-dose CsA but rare with higher CsA doses. In this new model of accelerated GCA in rats, immune-mediated antigen-dependent vasculopathy as a result of inadequate immunosuppresion is fundamental in the development of GCA, which appeared equally in epicardial arteries and intramyocardial arterioles. CsA prevents GCA in a dose-dependent fashion in the rat allograft.

Intramyocardial arterial narrowing in dogs with subaortic stenosis.

Earlier studies have described intramyocardial arterial narrowing based on hyperplasia and hypertrophy of the vessel wall in dogs with subaortic stenosis (SAS). In theory, such changes might increase the risk of sudden death, as they seem to do in heart disease in other species. This retrospective pathological study describes and quantifies intramyocardial arterial narrowing in 44 dogs with naturally occurring SAS and in eight control dogs. The majority of the dogs with SAS died suddenly (n=27); nine had died or been euthanased with signs of heart failure and eight were euthanased without clinical signs. Dogs with SAS had significantly narrower intramyocardial arteries (P<0.001) and more myocardial fibrosis (P<0.001) than control dogs. Male dogs and those with more severe hypertrophy had more vessel narrowing (P=0.02 and P=0.02, respectively), whereas dogs with dilated hearts had slightly less pronounced arterial thickening (P=0.01). Arterial narrowing was not related to age, but fibrosis increased with age (P=0.047). Dogs that died suddenly did not have a greater number of arterial changes than other dogs with SAS. This study suggests that most dogs with SAS have intramyocardial arterial narrowing and that the risk of dying suddenly is not significantly related to the overall degree of vessel obliteration.