The effect of irisin on the ultrastructure of the thoracic aorta in rat: A morphometric study.

BACKGROUND: One of the most recent hormones to be identified and isolated is irisin, extracted from mouse skeletal muscle in 2012. Irisin has been proven to alter blood pressure, which has an impact on blood vessels, enhance endothelial functions, and prevent injury to endothelial cells. The current study aimed to study the effect of irisin on the ultrastructure of the rat thoracic aorta using the transmission electron microscope (TEM). MATERIALS AND METHODS: Twenty female rats were recruited for this study and divided into a control group (non-injected), and four experimental groups (injected groups) each consisting of 4 rats. The experimental groups were injected intraperitoneally with different doses of irisin (250ng/mL, 500ng/mL, 1000ng/mL, and 2000ng/mL) twice a week for 4weeks. Then, the descending thoracic aorta of all experimental rats were resected and proceeded with imaging. RESULTS: The results of this study showed a change in the thickness of the tunica intima, internal elastic lamina, elastic lamellae, and external elastic lamina concerning increasing injected irisin concentration. While there was a significant increase in the thickness of tunica media (P<0.0001) and smooth muscle cells (P<0.05). Also, the results showed a significant increase in the number of elastic lamellae in the tunica media (P<0.0001). CONCLUSION: Irisin had a major impact on the elasticity of the rat thoracic aorta wall, suggesting that it influences the growth factors of the wall and activates smooth muscle cells in addition to endothelial cells.

Rosuvastatin alleviates the development of monocrotaline-induced pulmonary hypertension in rats.

Statins can increase endothelial function through enhancement of the expression and activity of endothelial nitric oxide synthase (eNOS). The aim of this study is to evaluate the effect of rosuvastatin on the number of circulating endothelial progenitor cells (EPCs) and endothelial expression of eNOS in monocrotaline-induced pulmonary hypertensive rats. Sixty Sprague-Dawley (SD) rats were divided into three groups of 20: control (group A), pulmonary hypertension (PAH) + rosuvastatin group (group B), and PAH (group C). Monocrotaline (MCT; 60 mg/kg) was injected (intraperitoneally) to induce PAH. Rats in group B received rosuvastatin [10 mg/(kg. day)] for 2 weeks. Peripheral blood (5 mL) was aspirated from the femoral artery of each rat before and after 2 weeks of treatment. Mononuclear cells were isolated and subcultured to obtain EPCs. Small and moderately sized pulmonary arteries were collected 2 weeks later for histological analyses. eNOS gene expression in endothelial cells of pulmonary arteries were then determined at mRNA and protein levels. eNOS expression at mRNA and protein levels and the number of circulating EPCs were reduced significantly in groups B and C compared with group A (P less than 0.05), and a significant difference between group B and group C (P less than 0.05) was observed. Vascular remodeling in small and moderately sized pulmonary arteries was attenuated markedly in group B compared with group C. These results suggest that rosuvastatin can ameliorate the remodeling of pulmonary arteries in MCT-induced PAH rats by increasing the number of circulating EPCs and eNOS upregulation.

Continuous exposure to low amplitude extremely low frequency electrical fields characterizing the vascular streaming potential alters elastin accumulation in vascular smooth muscle cells.

In normal development and pathology, the vascular system depends on complex interactions between cellular elements, biochemical molecules, and physical forces. The electrokinetic vascular streaming potential (EVSP) is an endogenous extremely low frequency (ELF) electrical field resulting from blood flowing past the vessel wall. While generally unrecognized, it is a ubiquitous electrical biophysical force to which the vascular tree is exposed. Extracellular matrix elastin plays a central role in normal blood vessel function and in the development of atherosclerosis. It was hypothesized that ELF fields of low amplitude would alter elastin accumulation, supporting a link between the EVSP and the biology of vascular smooth muscle cells. Neonatal rat aortic smooth muscle cell cultures were exposed chronically to electrical fields characteristic of the EVSP. Extracellular protein accumulation, DNA content, and electron microscopic (EM) evaluation were performed after 2 weeks of exposure. Stimulated cultures showed no significant change in cellular proliferation as measured by the DNA concentration. The per-DNA normalized protein in the extracellular matrix was unchanged while extracellular elastin accumulation decreased 38% on average. EM analysis showed that the stimulated cells had a 2.85-fold increase in mitochondrial number. These results support the formulation that ELF fields are a potential factor in both normal vessel biology and in the pathogenesis of atherosclerotic diseases including heart disease, stroke, and peripheral vascular disease.

A comparative ultrastructural study of a new type of autoschizis versus a survival cellular mechanism that involves cell membranes of cerebral arteries in humans.

The authors analyzed by transmission electron microscopy the modifications of plasmalemma and nuclear envelope in the cerebral arterial wall in humans. Their ultrastructural observations are performed on the tunica media and endothelium. During autoschizis, some smooth muscle cells showed deep invaginations of the nuclear envelope with multiple craters that disintegrate the nucleus, whereas in the endothelium repetitive invaginations of plasmalemma lead to cell demise by cytoplasmic self-excisions. During survival mechanism, a perinuclear constriction of plasmalemma occurs, which conserves nucleus and cytoskeleton, and only a segregated cytoplasmic area, without organelles, is removed in lumen.

Role of echocardiographic left ventricular mass and carotid intima-media thickness in the cardiovascular risk assessment of asymptomatic patients with type 2 diabetes mellitus.

BACKGROUND: Standard cardiovascular (CV) risk assessment may underestimate risk in people with type 2 diabetes mellitus (T2DM). Cardiac and vascular imaging to detect subclinical disease may augment risk prediction. This study investigated the association between CV risk, left ventricular hypertrophy (LVH) and carotid intima-media thickness (CIMT) in patients with T2DM free of CV symptoms. METHODS: People with T2DM without known CV disease were recruited from general practice. The 5-year risk of CV events was calculated using an adjusted Framingham equation and the prevalence of LVH and abnormal CIMT across bands of CV risk assessed. In those at intermediate risk, the number needed to scan (NNS) to reclassify one person to high risk was calculated across the group and compared in those above and below 55 years. The association between LV mass and CIMT was also assessed. RESULTS: Mean age 57 years (SD11), 51% female. Median 5-year CV risk 14.3% (interquartile range 10.3, 19.5), 51% had LVH (American Society of Echocardiography criteria) and 31% an abnormal CIMT (age and sex criteria). In the 52% at intermediate risk, 37% had LVH and 36% an abnormal CIMT. The NNS was 1.7 using both imaging techniques, 2.7 using cardiac imaging alone or 2.8 using vascular imaging alone. Almost twice as many people >55 years had an abnormal CIMT than those <55 years. CONCLUSIONS: Cardiac and vascular imaging to detect subclinical disease can be used to augment prediction of CV risk in people with T2DM at intermediate risk. The value of reclassifying risk is as yet unproven and requires outcome data from intervention studies.

Ultrastructural analysis of vascular calcifications in uremia.

Accelerated intimal and medial calcification and sclerosis accompany the increased cardiovascular mortality of dialysis patients, but the pathomechanisms initiating microcalcifications of the media are largely unknown. In this study, we systematically investigated the ultrastructural properties of medial calcifications from patients with uremia. We collected iliac artery segments from 30 dialysis patients before kidney transplantation and studied them by radiography, microcomputed tomography, light microscopy, and transmission electron microscopy including electron energy loss spectrometry, energy dispersive spectroscopy, and electron diffraction. In addition, we performed synchrotron x-ray analyses and immunogold labeling to detect inhibitors of calcification. Von Kossa staining revealed calcification of 53% of the arteries. The diameter of these microcalcifications ranged from 20 to 500 nm, with a core-shell structure consisting of up to three layers (subshells). Many of the calcifications consisted of 2- to 10-nm nanocrystals and showed a hydroxyapatite and whitlockite crystalline structure and mineral phase. Immunogold labeling of calcification foci revealed the calcification inhibitors fetuin-A, osteopontin, and matrix gla protein. These observations suggest that uremic microcalcifications originate from nanocrystals, are chemically diverse, and intimately associate with proteinaceous inhibitors of calcification. Furthermore, considering the core-shell structure of the calcifications, apoptotic bodies or matrix vesicles may serve as a calcification nidus.

Age-dependent ultrastructural changes of coronary artery in spontaneously hypertensive rats.

The age-dependent differences in basic cardiovascular parameters, geometry and structure of coronary arteries between Wistar and spontaneously hypertensive rats (SHR) were evaluated. SHR of the age 3-, 9-, 17-, and 52-week and age-matched Wistar rats were used. Blood pressure (BP) was measured by the plethysmographic method. Animals were perfused with a glutaraldehyde fixative under pressure of 90 mmHg (3-week-old) and 120 mmHg (9-, 17-, 52-week-old). Coronary arteries were processed for electron microscopy. The proportions and cross sectional areas (CSA) of extracellular matrix in intima and media, endothelial and muscle cells were determined by point counting method. Cardiac hypertrophy and except of 3-week-old rats also BP increase and coronary wall hypertrophy was found in all ontogenic periods in SHR compared to Wistar rats. Arterial wall hypertrophy was evoked by increase of CSA of medial extracellular matrix and smooth muscle cells. In 52-week-old SHR, CSA of muscle cells did not differ from that in 17-week-old SHR but the CSA of intimal and medial extracellular matrix significantly increased. The CSA of endothelial cells and CSA of intimal extracellular matrix were increased only in 52-week-old SHR. The independency between BP and trophicity of individual components of the coronary wall during ontogeny of SHR was documented.

Quantitative not qualitative histology differentiates aneurysmal from nondilated ascending aortas and reveals a net gain of medial components.

Medial degeneration is a common histopathological finding in aortopathy and is considered a mechanism for dilatation. We investigated if medial degeneration is specific for sporadic thoracic aortic aneurysms versus nondilated aortas. Specimens were graded by pathologists, blinded to the clinical diagnosis, according to consensus histopathological criteria. The extent of medial degeneration by qualitative (semi-quantitative) assessment was not specific for aneurysmal compared to nondilated aortas. In contrast, blinded quantitative assessment of elastin amount and medial cell number distinguished aortic aneurysms and referent specimens, albeit with marked overlap in results. Specifically, the medial fraction of elastin decreased from dilution rather than loss of protein as cross-sectional amount was maintained while the cross-sectional number, though not density, of smooth muscle cells increased in proportion to expansion of the media. Furthermore, elastic lamellae did not thin and interlamellar distance did not diminish as expected for lumen dilatation, implying a net gain of lamellar elastin and intralamellar cells or extracellular matrix during aneurysmal wall remodeling. These findings support the concepts that: (1) medial degeneration need not induce aortic aneurysms, (2) adaptive responses to altered mechanical stresses increase medial tissue, and (3) greater turnover, not loss, of mural cells and extracellular matrix associates with aortic dilatation.

Dose-dependent ultrastructural and morphometric alterations after erythropoietin treatment in rat femoral artery vasospasm model.

PURPOSE: Cerebral vasospasm is the common cause of poor outcome after aneurysmal subarachnoid hemorrhage (aSAH). Although many agents are experimentally and clinicaly used to protect or recover from vasospasm, an effective neurotherapeutic drug is still missing. Erythropoietin (EPO) is recently a promising candidate. The aim of this study is to investigate the dose-dependent effects of recombinant human EPO (rhEPO) on arterial wall in a rat femoral artery vasospasm model. METHODS: Thirty two animals were divided into four groups: vasospasm without any treatment (group A), vasospasm +250 IU/kg rhEPO group (group B), vasospasm +500 IU/kg rhEPO group (group C), and control group (group D). Rat femoral artery vasospasm model was used. For groups B and C, 7 days of 250 IU/kg and 500 IU/kg intraperitoneal rhEPO in 0.3 ml saline were administered respectively; and for groups A and D, 0.3 ml saline were administered intraperitoneally without any treatment. After 7 days, histological and morphometric analyses were carried out. RESULTS: Vasospasm alone group demonstrated the highest vessel wall thicknesses, comparing to other groups (p < 0.001). While for groups B and C, vessel wall thickness values were significantly higher than the control group (p < 0.001), between these two groups, there was no significant difference achieved (p > 0.05). CONCLUSION: In our study, there was no significant difference between the two rhEPO treatment groups, but rhEPO treatment was shown to be histologically and morphometrically effective in vasospasm. However, if dosage of EPO treatment is augmented, successful results may be achieved.

Morphological changes in varicocele veins: ultrastructural study.

BACKGROUND: Varicocele consists of dilatation of the pampiniform venous plexus and the internal spermatic veins. It is present in 15% of male population and is a common cause of male infertility. OBJECTIVE: To describe the normal structure of the internal spermatic vein and the morphological changes in grade 3 varicocele. METHODS: The authors dissected and analyzed a 2- to 3-cm tract of the pampiniform venous plexus of 20 patients undergoing varicocelectomy for left varicocele and of 10 consecutive patients undergoing surgery for left inguinal hernia. The histological examination was performed with hematoxylin­eosin and Masson trichrome stains. The ultrastructural evaluation was done using both scanning and transmission electron microscopy. RESULTS: Compared with normal internal spermatic veins, varicocele veins showed narrowing and/or obliteration of the lumens, destruction of the endothelial cells, invagination of the intima, and deposition of collagen bundles in the media (light microscopy). The ultrastructural changes in varicocele veins included elongation of the endothelial cells with features of cellular damage, loss of the internal elastic lamina, and the appearance of ghost bodies and degenerative vacuoles in the subendothelial layer. CONCLUSIONS: The authors believe this is the first report analyzing ultrastructual changes in normal human internal spermatic vein samples and in varicocele. The underlying molecular mechanisms of these changes await further studies.

Effect of collagen fibres and elastic lamellae content on the mechanical behaviour of abdominal aortic aneurysms.

PURPOSE: The main purpose of this study was a detailed analysis of the mechanical and structural characteristics of human abdominal aneurysms in comparison with normal abdominal aortae and determination of the correlations between their mechanical behaviour and the microstructural content. METHODS: Various mechanical properties, i.e., mechanical failure properties, elastic moduli, inflection point coordinates, index of anisotropy and incompressibility were determined under uniaxial loading conditions in the circumferential and axial directions. Constitutive parameters were derived from the commonly used constitutive model proposed by Holzapfel et al. [9]. The microstructural arrangement was examined by histological staining supported by scanning electron microscopy analysis. The content of collagen fibres and elastic lamellae was tested in relation to mechanical properties and constitutive parameters. RESULTS: Significant differences were found in the microstructural arrangement and layer composition of the aneurysmal specimens, compared to the normal aorta group. The mechanical properties and constitutive parameters of the aneurysmal specimens were significantly altered, indicating a weakening of the load-bearing properties of the walls of the aneurysms. A comparative analysis discovered significant correlations between structural composition and mechanical parameters, in particular with respect to the number of collagen fibres and failure stress, which can be important for clinical evaluation of abdominal aortic aneurysm (AAA) rupture. CONCLUSIONS: Changes in the content of collagen fibres and elastic lamellae correlate with mechanical and constitutive parameters, indicating AAA severity.

A detailed microscopic study of the changes in the aorta of experimental model of postmenopausal rats fed with repeatedly heated palm oil.

Hypercholesterolaemia, increase in lipid peroxidation and hyperhomocysteinaemia may contribute to the pathogenesis of atherosclerosis. This study was performed to examine the effects of repeatedly heated palm oil mixed with 2% cholesterol diet on atherosclerosis in oestrogen-deficient postmenopausal rats. Ovariectomy causes disruption of tunica intima layer of the rat aorta simulating a postmenopausal condition in females. Twenty-four ovariectomized female Sprague-Dawley rats were divided into four groups. The control group received 2% cholesterol diet without palm oil. A diet with 2% cholesterol content fortified with fresh, once-heated and five-times-heated palm oil was given to the other treatment groups. The rats were sacrificed at the end of 4 months of study and the aortic arch tissue was processed for histomorphometry and electron microscopy. On observation, there was disruption of the intimal layer of the ovariectomized rat aorta. There was no obvious ultrastructural change in the aorta of the rats fed with fresh palm oil. The ultrastructural changes were minimal with once-heated palm oil, in which there was a focal disruption of the endothelial layer. The focal disruption was more pronounced with five-times-heated palm oil. The results of this study show that the ingestion of fresh palm oil may have a protective effect on the aorta but such a protective action may be lost when the palm oil is repeatedly heated. The study may be clinically important for all postmenopausal women who are susceptible to atherosclerosis.

Long-term effect of losartan administration on blood pressure, heart and structure of coronary artery of young spontaneously hypertensive rats.

Alterations in geometry and structure of coronary arteries have marked consequences on blood flow to the respective area. We evaluated long-term effect of losartan on blood pressure (BP), heart weight/body weight (HW/BW), geometry and structure of septal branch of coronary artery (RS) of young SHR and Wistar rats. Four-week-old Wistar rats and SHR were used. Losartan was administered (20 mg/kg/day) in drinking water by gavage for 5 weeks. BP was measured by plethysmographic method. Cardiovascular system was perfused with a fixative (120 mm Hg). RS was processed for electron microscopy. Wall thickness of intima + media (WT), inner diameter (ID), cross-sectional area of intima + media (CSA), volume densities (VD) of endothelial cells (EC), extracellular matrix (ECM) of intima, smooth muscle cells (SMC) and ECM of media were evaluated. BP of 4-week-old SHR did not differ from that of Wistar rats. BP, HW/BW, WT, CSA, WT/ID, CSAs of SMC, ECM of media were increased in 9-week-old SHR, whereas their VD and CSA of EC were decreased. Losartan administration decreased BP and HW/BW in both groups. Geometry of RS was affected only in SHR (reduction of WT, CSA, WT/ID and increased of ID, circumferential tension, VD and CSA of EC). Losartan administration reduced BP and myocardial mass in both groups and beneficially affected geometry and structure of coronary artery in SHR.

Comparison of markers of oxidative stress, inflammation and arterial stiffness between incident hemodialysis and peritoneal dialysis patients--an observational study.

BACKGROUND: Patients on peritoneal and hemodialysis have accelerated atherosclerosis associated with an increase in cardiovascular morbidity and mortality. The atherosclerosis is associated with increased arterial stiffness, endothelial dysfunction and elevated oxidative stress and inflammation. The aims of this study are to investigate the effects of peritoneal and hemodialysis on arterial stiffness, vascular function, myocardial structure and function, oxidative stress and inflammation in incident patients with end stage kidney disease. METHODS: This is an observational study. Eighty stage five CKD patients will be enrolled and followed for one-year. Primary outcome measures will be changes in 1) arterial stiffness measured by aortic pulse wave velocity, 2) oxidative stress assessed by plasma F2 isoprostanes and 3) inflammation measured by plasma pentraxin-3. Secondary outcomes will include additional measures of oxidative stress and inflammation, changes in vascular function assessed using the brachial artery reactivity technique, carotid artery intimal medial thickness, augmentation index and trans thoracic echocardiography to assess left ventricular geometry, and systolic and diastolic function. Patients will undergo these measures at baseline (6-8 weeks prior to starting dialysis therapy), then at six and 12 months after starting dialysis. DISCUSSION: The results of this study may guide the choice of dialysis modality in the first year of treatment. It may also lead to a larger study prospectively assessing the effect of dialysis modality on cardiovascular morbidity and mortality. TRIAL REGISTRATION: ACTRN12609000049279.

Relationship between renal resistive index and early target organ damage in patients with never-treated essential hypertension.

The aim of our study was to evaluate renal resistive index (RI) value in never treated hypertensive patients in relation to ambulatory blood pressure measurement (ABPM) values and early target organ damage. The study included 318 subjects: 223 patients with never treated essential hypertension (mean age 37.1 years) and 95 normotensive healthy subjects (mean age 37.9 years). ABPM, echocardiography and carotid and renal arteries duplex color Doppler examinations were performed. RI values in patients with never treated essential hypertension were no different from the normotensive control group (0.59 +/- 0.05 vs 0.59 +/- 0.05; NS). In the untreated patients RI correlated significantly with 24-h pulse pressure (r=0.234; p<0.01) and ambulatory arterial stiffness index (AASI) values (r=0.274; p<0.001), intima-media thickness (IMT) (r=0.249; p<0.001), E'/A' (rho= -0.279; p<0.001) and relative wall thickness (RWT; r=0.185; p<0.01). In the multivariate stepwise analysis, RI values correlated independently with carotid IMT (beta=0.272; p=0.020) and 24-h AASI values (beta=0.305; p=0.009). In normotensive healthy controls, significant independent correlation between RI and carotid IMT and 24-h AASI values were also found. Our study may indicate limited value of RI in differentiating patients with uncomplicated hypertension with healthy controls. Renal resistive values were independently correlated with carotid IMT and AASI. These may suggest that renal vascular resistance is related to two markers for cardiovascular events both in the hypertensive and normotensive subjects.

Histopathological comparison of vascular wall damage created by external cross-clamp and endoluminal balloon occlusion techniques.

AIM: Almost all cross-clamps utilized in vascular surgery, even atraumatic clamps, have been shown to cause mechanical damage to the vascular wall. In recent years, surgical procedures using an endoluminal balloon technique have been reported as an alternative occlusion strategy. This study discusses the histopathological characteristics and comparison between vascular wall damage secondary to the two occlusion techniques in the early postoperative period. METHODS: Twelve adult rabbits were divided into two experimental groups: the clamp group (N. = 6) and the balloon group (N. = 6). External cross-clamp occlusion was applied to the abdominal aorta for 30 minutes via laparotomy in the clamp group. In the balloon group, occlusion was applied for 30 minutes by inflating the catheter balloon, which was inserted through the iliac artery and advanced into the abdominal aorta. The appropriate aortic segments were subsequently extracted in both groups and tissue samples were examined by light and electron microscopy. Finally, the samples were scored for grade of tissue damage. RESULTS: In both experimental groups, tissue damage was apparent. In the investigations carried out under light microscopy, it was observed that the damage caused by balloon occlusion was remarkably less than the damage caused by the cross-clamp technique. In the balloon group, eight tissue samples (66.7%) had grade 1 damage. On the other hand, five tissue samples had grade 3 damage, all of which were in the clamp group. Investigation by electron microscopy revealed that greater intimal, medial, and adventitial damage occurred in the vascular walls of the clamp group samples, and this also corresponded with an increase in immune response and intraluminal thrombosis. CONCLUSION: External clamp and internal balloon occlusion techniques applied to the aorta were compared, and widespread intimal and medial damage were observed in both techniques. However, endoluminal occlusion of the aorta should be the technique of choice in properly selected cases, since it results in lower damage grades, and it should also be used if application of an external clamp is technically difficult.

Effect of alpha lipoic acid on oxidative stress and vascular wall of diabetic rats.

UNLABELLED: PREMISES AND OBJECTIVES: Antioxidant plays an important role in preventing the progression of diabetes mellitus (DM) complications. The aim of the present study was to investigate the effect of alpha lipoic acid (ALA) supplementation on plasma lipid, oxidative stress and vascular changes in diabetic rats. MATERIAL AND METHODS: Diabetes was induced by a single intravenous injection of streptozotocin (STZ) (50 mg/kg). The diabetic rats were divided into two groups: (i) supplemented group with ALA (100 mg/kg/day) and (ii) non-supplemented group without ALA. Non-diabetic rats (NDM) formed the control group, which received saline injection. RESULTS: Following eight weeks of supplementation, fasting blood glucose (FBG) and glycosylated hemoglobin (HBA1c) in ALA-supplemented rats was found to be significantly lower than the non-supplemented group. ALA-supplementation also improved dyslipidemia that occurred in diabetic rats. ALA-supplementation also significantly increased plasma superoxide dismutase (SOD) activity and vitamin C level as compared to the No Suppl group. The increase in plasma and aorta malondealdehyde + 4-hydroxynonenal (MDA + 4-HNE) levels were also inhibited and the levels of oxidative DNA damage of peripheral lymphocytes were significantly reduced. Electron microscopic examination of thoracic aorta revealed that normal tissue organization was disrupted in STZ-diabetic rats with ALA-supplementation reducing the changes in the vascular morphology. CONCLUSIONS: It is concluded that ALA has the potential in preventing the alteration of vascular morphology in diabetic rats probably through the improvement of glycemic status and dyslipidemia as well as its antioxidant activities.

Some segmental morphological and morphometrical features of the intima and media of the aortic wall in Chinchilla lanigera.

BACKGROUND: The aim of this study is to describe the morphology, morphometry and ultrastructure of segments of the thoracic and abdominal aorta portions in Chinchilla lanigera. Thickness measurements of the tunica intima and media complex of the aorta were taken. MATERIALS AND METHODS: In all observed specimens, the thickness values for the tunica intima and media complex of the cranial thoracic aorta were significantly higher (mean: 702.19 µm) when compared to the values of other analysed aortic segments (means: 354.18 µm; 243.55 µm). Complex statistical methods were used to assess the differences between various aortic segments. RESULTS AND CONCLUSIONS: The components of the vessel walls show variations in structure and thickness, presumably due to an adaptation to functional demand.

Segment-specific genetic effects on carotid intima-media thickness: the Northern Manhattan study.

BACKGROUND AND PURPOSE: Carotid intima-media thickness (IMT) is a surrogate marker of subclinical atherosclerosis and a strong predictor of stroke and myocardial infarction. The object of this study was to determine the association between carotid IMT and 702 single nucleotide polymorphisms in 145 genes. METHODS: B-mode carotid ultrasound was performed among 408 Hispanics from the Northern Manhattan Study. The common carotid artery IMT and bifurcation IMT were phenotypes of interest. Genetic effects were evaluated by the multivariate regression model adjusting for traditional vascular risk factors. For each individual, we calculated a gene risk score (GRS) defined as the total number of the significant single nucleotide polymorphisms in different genes. Subjects were then divided into 3 GRS categories using the 2 cutoff points: mean GRS +/-1 SD. RESULTS: We identified 6 significant single nucleotide polymorphisms in 6 genes for common carotid artery IMT and 7 single nucleotide polymorphisms in 7 genes for bifurcation IMT using the probability value of 0.005 as the significant level. There were no common significant genes for both phenotypes. The most significant genes were the tissue plasminogen activator (P=0.0005 for common carotid artery IMT) and matrix metallopeptidase-12 genes (P=0.0004 for bifurcation IMT). Haplotype analysis did not yield a more significant result. Subjects with GRS >or=9 had significantly increased IMT than those with GRS

Characteristics and baseline clinical predictors of future fatal versus nonfatal coronary heart disease events in older adults: the Cardiovascular Health Study.

BACKGROUND: Although >80% of annual coronary heart disease (CHD) deaths occur in adults aged >65 years and the population is aging rapidly, CHD event fatality and its predictors in the elderly have not been well described. METHODS AND RESULTS: The first myocardial infarction (MI) or CHD death among the 5888 adults aged > or =65 years occurring during enrollment in the Cardiovascular Health Study during 1989-2001 was identified and adjudicated. Characteristics measured at examinations before the event were examined for associations with case fatality (death before hospitalization or hospital discharge) and for differences in predictors by demographics or clinical history. During a median follow-up of 8.2 years, 985 CHD events occurred, of which 30% were fatal. Case fatality decreased slightly over time, ranging from 28% to 30% per year in the early 1990s versus 23% by 2000-2001; with adjustment for age at MI and gender, there was a 6% lower odds of fatality with each successive year (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.90 to 0.98). Case fatality was similar by race and gender but higher with age and prior CHD (MI, angina, or revascularization). When considered alone, many subclinical disease measures, such as common carotid intima-media thickness, ankle-arm index, left ventricular mass by ECG, and a major ECG abnormality, and traditional risk factors, such as diabetes and hypertension, were associated with fatality. In multivariable analysis, independent predictors of fatality were prior congestive heart failure (OR, 3.20; 95% CI, 2.32 to 4.41), prior CHD rather than only history of MI (OR, 2.51; 95% CI, 1.84 to 3.43), diabetes (OR, 1.66; 95% CI, 1.10 to 2.31), and age (OR, 1.21 per 5 years; 95% CI, 1.07 to 1.37), adjusted for gender and each other. Prior congestive heart failure, regardless of left ventricular systolic function, age, gender, or prior CHD, conferred a > or =3-fold increased risk of fatality in almost all subgroups. CONCLUSIONS: Among community-dwelling older adults, CHD case fatality remains substantial, with easily identifiable risk factors that may be different from those that predict incident disease. In the elderly in whom the risk/benefit of therapies may be influenced by multiple competing comorbidities and care needs, risk stratification possibly may be improved further by focusing more aggressive care on specific patients, especially those with a history of congestive heart failure or prior CHD.