bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic modification of the vessel wall. Comparison of surgical and catheter-based techniques for delivery of recombinant adenovirus.
Authors: Willard J E , Landau C , Glamann D B , Burns D , Jessen M E , Pirwitz M J , Gerard R D , Meidell R S 
Published: June 2012

BACKGROUND
Gene transfer can potentially alter vessel wall biology and intervene in the pathogenesis of human disease. Although several methods for vector delivery have been described, systematic comparisons of these methods are unavailable. Therefore, this study compared three catheter-based strategies and a surgical technique to assess efficient and selective gene transfer to the vascular wall.

METHODS AND RESULTS
The common carotid arteries and internal jugular veins of New Zealand White rabbits were infected with recombinant adenovirus encoding either firefly luciferase or a nuclear-localizing variant of beta-galactosidase. Delivery of recombinant virus was achieved by one of four methods: (1) instillation within a surgically isolated vessel segment (dwell), (2) a double-balloon catheter, (3) a perforated balloon catheter (Wolinsky), or (4) an angioplasty balloon catheter coated with a hydrophilic adsorbent polymer (Hydrogel). Vessel segments were analyzed 4 days after infection for luciferase and beta-galactosidase activity and for the extent of injury to the vessel wall. Luciferase activity in vessels infected using the double-balloon method was substantially greater than that achieved by catheter-based methods (P < .05). The dwell and double-balloon methods yielded selective expression in intimal cells, whereas arteries infected using perforated or Hydrogel-coated balloon catheters demonstrated expression primarily in medial cells. Tissue injury was most pronounced with the perforated balloon catheter.

CONCLUSIONS
Prototype catheters permit relatively efficient direct gene transfer to vascular endothelium; however, delivery methods for targeting the medial cells are inefficient. Modifications are needed to optimize direct gene transfer and minimize tissue injury.
Angiotensin II receptor antagonist TCV-116 induces regression of hypertensive left ventricular hypertrophy in vivo and inhibits the intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro.
Authors: Kojima M , Shiojima I , Yamazaki T , Komuro I , Zou Z , Wang Y , Mizuno T , Ueki K , Tobe K , Kadowaki T 
Published: June 2012

BACKGROUND
Previous studies have demonstrated that angiotensin II (Ang II) acts as a growth-promoting factor directly on cardiac myocytes and that angiotensin-converting enzyme inhibitor induces regression of hypertrophied hearts both in experimental animals and in humans. These results suggest that the renin-angiotensin system (RAS) is involved in the formation of left ventricular hypertrophy (LVH). To elucidate the role of RAS in the progression of cardiac hypertrophy, we evaluated the effect of an Ang II receptor antagonist on LVH in spontaneously hypertensive rats (SHRs) and investigated the molecular mechanisms by which antagonizing Ang II receptors reduces cell hypertrophy of myocytes using the in vitro model of mechanical stretch.

METHODS AND RESULTS
In the in vivo study, we treated SHRs with the nonpeptide Ang II receptor antagonist TCV-116 (0.1, 1, or 10 mg/kg per day) or hydralazine (10 mg/kg per day). Blood pressure was measured by the tail-cuff method, and wall thickness of left ventricle was serially monitored using M-mode echocardiography. Rats were killed at the age of 13, 17, 21, or 25 weeks, and left ventricular (LV) weight, transverse diameter of cardiomyocytes, relative amount of V3 myosin heavy chain (MHC), and degree of interstitial collagen accumulation were examined. Untreated SHRs progressively developed severe hypertension, but treatment with TCV-116 or hydralazine inhibited the increase in blood pressure. Treatment with TCV-116 reduced LV weight, LV wall thickness, transverse diameter of myocytes, relative amount of V3 MHC, and interstitial fibrosis, whereas treatment with hydralazine slightly prevented an increase in LV wall thickness but did not exert significant reduction in other parameters. In the in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes and mechanically stretched with or without pretreatment of CV-11974 (an active metabolite of TCV-116), and [3H]phenylalanine incorporation, activity of mitogen-activated protein (MAP) kinase, and c-fos mRNA expression were analyzed. Pretreatment of cultured cardiomyocytes with 10(-7) mol/L CV-11974 inhibited an increase in [3H]phenylalanine incorporation, MAP kinase activity, and c-fos gene expression induced by stretch of cardiomyocytes.

CONCLUSIONS
The Ang II receptor antagonist TCV-116 induced regression of cardiac hypertrophy and had cardioprotective effects on hypertrophied myocardium in vivo, and antagonizing Ang II receptors inhibited intracellular signaling of stretch-mediated cardiomyocyte hypertrophy in vitro. These results suggest a crucial role of the cardiac RAS in the development of LVH produced by pressure overload.
Exercise induces cardiac dysfunction in both moderate, compensated and severe hypertrophy.
Authors: Hittinger L , Patrick T , Ihara T , Hasebe N , Shen Y T , Kalthof B , Shannon R P , Vatner S F 
Published: June 2012

BACKGROUND
Ventricular hypertrophy begins as a physiological adaptation to cardiac overload but progresses to a pathological state. We examined whether the extent of hypertrophy influenced the response to exercise in terms of its effects on regional and global ventricular function and transmural myocardial blood flow distribution.

METHODS AND RESULTS
Left ventricular (LV) hypertrophy was induced by aortic banding in puppies. The effects of treadmill exercise were compared in sham-operated control dogs (n = 7) and in dogs with moderate LV hypertrophy (47% increase in LV wt/body wt, n = 7) with normal baseline levels of LV systolic and diastolic wall stress and dogs with severe LV hypertrophy (85% increase in LV wt/body wt, n = 18), which exhibited elevated levels of LV systolic wall stress at baseline. The dogs with severe LV hypertrophy were further subdivided into those with either elevated or normal baseline levels of LV end-diastolic pressure and wall stress. The response to exercise in dogs with moderate LV hypertrophy was directionally similar to that of sham-operated control dogs for systemic hemodynamics and global and regional LV function, ie, full and subendocardial wall thickening rose, as did mean and diastolic arterial pressures, shortening fraction, and Vcf. The endocardial/epicardial blood flow ratio did not fall during exercise in these two groups. However, relations comparing either LV shortening, Vcf, or wall thickening with LV systolic wall stress during exercise demonstrated depressed myocardial function in the dogs with moderate LV hypertrophy. In contrast, in dogs with severe LV hypertrophy, exercise reduced LV shortening fraction, Vcf, mean and diastolic arterial pressures, and full and subendocardial wall thickening, and the endocardial/epicardial blood flow ratio fell to 0.73 +/- 0.07. There were no differences observed between the two subgroups with severe LV hypertrophy, but the global and regional wall function responses to exercise were more severely impaired than those in dogs with moderate LV hypertrophy.

CONCLUSIONS
Responses of global and regional LV function and transmural myocardial blood flow distribution to exercise were clearly abnormal in dogs with severe LV hypertrophy with elevated baseline levels of LV systolic wall stress whether or not baseline levels of LV end-diastolic wall stress were elevated. Thus, it required more severe LV hypertrophy as well as elevated levels of LV wall stress to elicit qualitatively abnormal regional and global hemodynamic responses to exercise. However, even with moderate LV hypertrophy, which was well compensated under baseline conditions, qualitatively impaired contraction-afterload relations were observed during the stress of exercise.
Mechanism of altered patterns of left ventricular filling during the development of congestive heart failure.
Authors: Ohno M , Cheng C P , Little W C 
Published: June 2012

BACKGROUND
The mechanism of the alterations in the pattern of left ventricular (LV) filling during the development of congestive heart failure (CHF) is not fully understood.

METHODS AND RESULTS
We studied six conscious dogs instrumented to measure LV and left atrial (LA) pressures and LV volume as CHF was induced by rapid pacing. Diastolic filling dynamics were serially measured over 4 weeks during normal sinus rhythm. Four days after we initiated pacing, the peak early diastolic filing rate decreased from 108 +/- 24 to 88 +/- 27 mL/s (P < .05) as the maximal early diastolic LA-LV pressure gradient decreased associated with a slowing of the rate of LV relaxation. Subsequently, the peak early filling rate progressively increased, returning to control at 1 week, and by the fourth week, it had increased to 168 +/- 39 mL/s (P < .05). These changes in early filling rates occurred as the maximal early diastolic LA-LV pressure gradient increased in association with a progressive increase in LV pressure despite further progressive slowing of the rate of LV relaxation. Throughout the development of CHF, peak early filling rate and the maximal LA-LV pressure gradient correlated (r = .99, P < .001). The early filling deceleration rate increased and deceleration time progressively decreased over the 4 weeks as LV stiffness and net LA plus LV stiffness increased (P < .05). As predicted by a theoretical analysis, the deceleration time was linearly related to the reciprocal of the square root of LV stiffness (r = .94, P < .01).

CONCLUSIONS
Early in CHF, slowing of LV relaxation reduces the maximal early diastolic LA-LV pressure gradient, decreasing the peak early filling rate. As CHF progresses, this is overcome by an increase in LA pressure that augments the early diastolic LA-LV pressure gradient, increasing peak early filling rate. Increasing LV stiffness during the development of CHF progressively shortens the early filling deceleration time and augments the early filling deceleration rate. These observations suggest that the early filling deceleration time reflects LV stiffness.
Redistribution of 99mTc-sestamibi and 201Tl in the presence of a severe coronary artery stenosis.
Authors: Sinusas A J , Bergin J D , Edwards N C , Watson D D , Ruiz M , Makuch R W , Smith W H , Beller G A 
Published: June 2012

BACKGROUND
99mTc-labeled methoxyisobutyl isonitrile (99mTc-sestamibi) is a myocardial perfusion agent that clears slowly from the myocardium. This study evaluates the early and late myocardial distributions of 99mTc-sestamibi and 201Tl in the presence of low-flow ischemia to determine whether 99mTc-sestamibi demonstrates rest "redistribution."

METHODS AND RESULTS
Low-flow ischemia was produced in 18 anesthetized, open-chest dogs by partial occlusion of the left anterior descending coronary artery. Dogs were injected intravenously with 99mTc-sestamibi, 301Tl, and radiolabeled microspheres during sustained low-flow ischemia. The hearts were excised either 20 minutes (group 1, 10 dogs) or 2.5 hours (group 2, 8 dogs) after injection for gamma well counting to evaluate the early and late myocardial distributions of these radiotracers, relative to microsphere flow. The early myocardial distributions of 99mTc-sestamibi and 201Tl were comparable and correlated with the flow deficit (group 1). We observed a significant difference in myocardial 201Tl (P = .005) and 99mTc-sestamibi (P < .0001) activities between groups 1 and 2 dogs relative to flow, suggesting some redistribution of both tracers. Myocardial slices were imaged postmortem with a gamma camera, and 99mTc-sestamibi defect intensity was quantified. There was excellent correlation (r = .97) between the early relative 99mTc-sestamibi defect intensity on postmortem images and the flow deficit (group 1). Among group 2 dogs, the correlation was good (r = .87), but the 99mTc-sestamibi defect was less severe than the flow deficit, again suggesting redistribution.

CONCLUSIONS
The myocardial distributions of 99mTc-sestamibi and 201Tl early after injection are comparable and proportional to flow. Under conditions of sustained low flow, there was detectable rest "redistribution" of 99mTc-sestamibi verified by both gamma well counting and high-resolution postmortem imaging of myocardial slices. Whether this degree of 99mTc-sestamibi rest redistribution will be detectable by serial clinical imaging remains uncertain. Nevertheless, these data suggest that imaging should be delayed after the resting injection of 99mTc-sestamibi when assessing myocardial viability in the presence of a critical stenosis.
Microvascular integrity indicates myocellular viability in patients with recent myocardial infarction. New insights using myocardial contrast echocardiography.
Authors: Ragosta M , Camarano G , Kaul S , Powers E R , Sarembock I J , Gimple L W 
Published: June 2012

BACKGROUND
Patency of the infarct-related artery (IRA) after acute myocardial infarction (AMI) may not reflect the magnitude of tissue perfusion. In animal models of AMI, myocardial cellular necrosis has been associated with extensive capillary damage. Because myocardial contrast echocardiography (MCE) can define the spatial distribution of microvascular perfusion, we hypothesized that it could be used in patients after recent AMI to distinguish myocardial regions that have an intact microvasculature and thus are viable from those without an intact microvasculature and thus are not viable.

METHODS AND RESULTS
One hundred five patients with a recent AMI (range, 1 day to 4 weeks; median, 8 days) who were undergoing cardiac catheterization were included in the study. Two-dimensional echocardiography was performed at baseline and repeated 1 month later to assess regional function within the infarct zone (scores of 1 to 5 indicating normal to dyskinetic segments, respectively). MCE was performed in the cardiac catheterization laboratory to assess microvascular perfusion within the infarct bed. A contrast score index was derived by assigning scores to individual segments within the infarct zone (0, 0.5, and 1 denoting no, intermediate, and homogeneous contrast effect, respectively) and deriving the average score within the infarct bed. Revascularization was performed as clinically indicated. Although the baseline wall motion score and the contrast score index were similar in the 90 patients with a patent IRA and the 15 patients with an occluded IRA (median +/- 1 interquartile range, 3 +/- 1 versus 3.5 +/- 1; P = .41), wall motion score 1 month later was significantly better in those with open IRAs compared with those with closed IRAs (2 +/- 2 versus 3 +/- 2, P = .05). In the 90 patients with an open IRA, a strong correlation was noted between wall motion score 1 month later and the contrast score index (rho = -.64, P < .001). On multivariate analysis, the best correlate of the 1-month wall motion score was the contrast score index.

CONCLUSIONS
In patients studied in the cardiac catheterization laboratory between 1 day and 4 weeks after AMI, an intact microvasculature as identified by MCE indicates myocardial regions that improve function 1 month later. This study demonstrates that microvascular patency is closely associated with myocardial cellular viability after AMI in humans.
Molecular evidence for induction of intracellular adhesion molecule-1 in the viable border zone associated with ischemia-reperfusion injury of the dog heart.
Authors: Youker K A , Hawkins H K , Kukielka G L , Perrard J L , Michael L H , Ballantyne C M , Smith C W , Entman M L 
Published: June 2012

BACKGROUND
Acute inflammation may play a role in injury during reperfusion following myocardial ischemia. Studies in vitro suggest that intracellular adhesion molecule-1 (ICAM-1) mediates neutrophil adherence to cardiac myocytes and neutrophil-mediated injury. We have shown cytokine activity in postischemic cardiac lymph sufficient to maximally express ICAM-1 on myocytes and that ICAM-1 mRNA is found in the previously ischemic myocardium early in reperfusion.

METHODS AND RESULTS
In the present study, we used in situ hybridization techniques to detect ICAM-1 mRNA and examine the cells of origin, relation to cell injury, and relation to inflammatory infiltration after 1 hour of ischemia and varying times of reperfusion. By 1 hour of reperfusion, ICAM-1 mRNA was detected in much of the ischemic myocardium, except in areas of contraction band necrosis. At 2 and 3 hours, a clear demarcation of necrotic areas surrounding ischemic areas of viable myocardium with ICAM-1 mRNA staining was present, and ICAM-1 mRNA staining increased with time. Nonischemic areas had no visible ICAM-1 mRNA staining in the first 3 hours. By 24 hours of reperfusion, ICAM-1 mRNA was present in both control and ischemic segments (excluding the necrotic areas) compatible with a generalized circulation of cytokines persistent at 24 hours. In the absence of reperfusion, ICAM-1 mRNA staining was not seen in the first 3 hours and was markedly reduced at 24 hours. The interface of viable and necrotic cells also contained the most extensive inflammatory infiltration.

CONCLUSIONS
Evidence is presented that induction of ICAM-1 mRNA has highly specific localization to ischemic but viable myocardium. Induction of ICAM-1 mRNA transcription in early reperfusion may render the viable "border zone" susceptible to neutrophil-induced injury.
Cytokine and murine coxsackievirus B3 myocarditis. Interleukin-2 suppressed myocarditis in the acute stage but enhanced the condition in the subsequent stage.
Authors: Kishimoto C , Kuroki Y , Hiraoka Y , Ochiai H , Kurokawa M , Sasayama S 
Published: June 2012

BACKGROUND
It has been shown that the development of coxsackievirus B3 (CB3) myocarditis is regulated by T cells and not by B cells. Interleukin-2 (IL-2) is a T-cell-derived cytokine that stimulates the growth of T cells. This study was carried out to determine the effects of IL-2 on CB3-infected BALB/c mice.

METHODS AND RESULTS
In two separate experiments, recombinant human IL-2 (5 x 10(4) U) was administered subcutaneously to 30 mice early (days 0 to 7) and 30 mice late (days 7 to 14) after infection with CB3. Each experiment had a control group of infected animals that did not receive IL-2. On days 7 and 10, splenic natural killer (NK) cell activity determined by 51Cr release assay and the distribution of myocardial lymphocyte subsets were compared in the treated and untreated groups. In the early treatment experiment, survival at 7 days was higher in treated compared with control animals, myocardial virus titers were lower, inflammatory cell infiltration was less (as was the severity of necrosis at the time the mice were killed), and NK cell activity was higher. However, in the late treatment experiment, survival at 14 days was lower in treated compared with control animals, and there was more infiltration, more severe necrosis, and more T-cell infiltration, but the NK cell activity did not differ significantly. In a third experiment similar to the late experiment described above but involving infected athymic nude mice, we confirmed the lack of effect of late in vivo administration of IL-2 on outcome.

CONCLUSIONS
IL-2 has the capacity to limit CB3 myocarditis by enhancing NK cell activity in the acute viremic stage, resulting in a reduction of cardiac pathology. However, in the subacute aviremic stage, in contrast, IL-2 exacerbates the course and severity of the disease by increasing the number of T cells infiltrating the myocardium. That is, IL-2 has differential effects on acute CB3 myocarditis. IL-2 is beneficial if treatment is given early but later in murine CB3 myocarditis.
Impact of left ventricular structure on the incidence of hypertension. The Framingham Heart Study.
Authors: Post W S , Larson M G , Levy D 
Published: June 2012

BACKGROUND
Left ventricular hypertrophy is often found very early in the course of hypertension. It is not known whether increased left ventricular mass contributes to the pathogenesis of hypertension. The purpose of this study was to examine the impact of left ventricular mass and other echocardiographically assessed cardiac structural features on the incidence of hypertension.

METHODS AND RESULTS
Subjects for this investigation included participants in the Framingham Heart Study and the Framingham Offspring Study who were normotensive at the baseline examination (systolic blood pressure, < 140 mm Hg; diastolic blood pressure, < 90 mm Hg; not receiving antihypertensive medications) and free of coronary heart disease, congestive heart failure, valvular heart disease, hypertrophic cardiomyopathy, diabetes mellitus, and renal insufficiency. The study sample included 1121 men (mean age, 44.4 years) and 1559 women (mean age, 45.6 years). Four years after the baseline examination, 202 men (18.0%) and 257 women (16.5%) were hypertensive (systolic blood pressure, > or = 140 mm Hg; diastolic blood pressure, > or = 90 mm Hg; or use of antihypertensive medications). Baseline echocardiographic left ventricular mass (P = .01) and the sum of septal and posterior left ventricular wall thicknesses (P = .02) were associated with progression to hypertension. After adjusting for sex, baseline age, systolic and diastolic blood pressures, body mass index, alcohol intake, and systolic blood pressure from an examination 8 years earlier, the odds ratio for developing hypertension for a 1-SD increment in left ventricular mass index was 1.20 (95% confidence interval, 1.04 to 1.39), and the odds ratio for a 1-SD increment in left ventricular wall thickness was 1.16 (95% confidence interval, 1.02 to 1.33).

CONCLUSIONS
In these normotensive adults, increased left ventricular mass and wall thickness were associated with the development of hypertension. Further studies are warranted to examine the utility of echocardiography in determining the need for antihypertensive therapy and to assess the effect of earlier intervention on the course of progression to hypertension.