bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Pregnancy in cyanotic congenital heart disease. Outcome of mother and fetus.
Authors: Presbitero P , Somerville J , Stone S , Aruta E , Spiegelhalter D , Rabajoli F
Published: June 2012

In a series of 416 women with congenital heart disease seen in the Royal Brompton National Heart and Lung Hospital, London, and the Hospital Giovanni Bosco, Torino, Italy, there were 822 pregnancies. The outcomes of 96 pregnancies in 44 patients with cyanotic congenital heart disease were studied. Patients with the Eisenmenger reaction were excluded. Patients were divided arbitrarily into groups according to the type of maternal congenital cardiac anomaly, and factors influencing maternal and fetal outcome were evaluated. The incidence of maternal cardiovascular complications was high (32%), with one death from endocarditis 2 months after delivery. Forty-one (43%) of 96 pregnancies resulted in a live birth; 15 (37%) were premature. Mean weight of full-term infants was 2575 g. Univariate analysis suggested that maternal disease, Ability Index, hemoglobin, and arterial oxygen saturation before the pregnancy were factors that discriminated between successful and unsuccessful fetal outcome, with hemoglobin and arterial oxygen saturation being the most important predictors. Women with cyanotic congenital heart disease can go through pregnancy with a low risk to themselves, with frequent treatable complications, but there is a high incidence of miscarriage, premature births, and low birth weights. An incidence of congenital heart disease in the fetus of 4.9% (2 of 41 live births) is higher than that found in the normal population.
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.
Angiotensin II increases plasminogen activator inhibitor type 1 and tissue-type plasminogen activator messenger RNA in cultured rat aortic smooth muscle cells.
Authors: van Leeuwen R T , Kol A , Andreotti F , Kluft C , Maseri A , Sperti G
Published: June 2012

BACKGROUND

The role of angiotensin as a vasoconstrictor is well established. Lately, several other actions of this hormone on vascular smooth muscle (VSM) cells have been recognized including the induction of hypertrophy and/or DNA synthesis. Platelet-derived growth factor (PDGF), a mitogen recently shown to increase plasminogen activator inhibitor type 1 (PAI-1) synthesis in VSM cells, shares with angiotensin II (Ang II) several steps of its intracellular signaling pathway.

METHODS AND RESULTS

The expression of PAI-1 and tissue-type plasminogen activator (TPA) mRNA in cultured rat VSM cells was studied. Northern blot analysis demonstrated a severalfold increase in the PAI-1 mRNA 3 to 8 hours after stimulation with 300 nmol/L Ang II. A similar response for TPA mRNA was observed. This induction did not require the synthesis of an intermediate protein or peptide because it was not affected by cycloheximide. In the cell-conditioned supernatant, the net result was an increase in PAI-1 activity from 4.18 +/- 1.8 to 13.2 +/- 6.8 IU/mL 6 hours after the addition of 300 nmol/L Ang II (mean +/- SD, P < or = .008, n = 6). The Ang II-induced increase in PAI activity was dose related, with a maximal effect at a concentration of 23 nmol/L (n = 3) and an ED50 of 3.3 +/- 1.5 nmol/L (n = 3). [Sar1-Ile8]angiotensin II, a specific competitive antagonist of Ang II, blocked 90 +/- 9% (n = 3) of the PAI activity induced by 10 nmol/L Ang II. In basal conditions, fibrin overlay zymography demonstrated the presence of free TPA. After stimulation with Ang II, lysis caused by the in situ dissociation of TPA was also present in the region of the TPA/PAI-1 complex. Angiotensin I (Ang I) elicited an increase in PAI activity similar to that obtained with equivalent doses of Ang II. Captopril (5 micrograms/mL), an inhibitor of the angiotensin-converting enzyme (ACE), completely prevented the Ang I effect, demonstrating that VSM cells display an ACE-like activity.

CONCLUSIONS

Recent research has demonstrated the existence of a localized vascular renin-angiotensin system. The finding that Ang II can potentially modulate the plasminogen activation in the arterial wall has important biological and therapeutical implications for the evolution of arterial wall thrombi and the migration of cells through the vessel wall in the genesis of atherosclerotic lesions. We speculate that the reduction in thrombotic events observed in patients with a previous myocardial infarction and in high-renin, hypertensive patients treated with ACE inhibitors could be due at least in part to the decreased production of PAI-1 by VSM cells caused by these agents.
Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading.
Authors: Haigney M C , Lakatta E G , Stern M D , Silverman H S
Published: June 2012

BACKGROUND

Studies have shown that the rise in intracellular ionized calcium, [Ca2+]i, in hypoxic myocardium is driven by an increase in sodium, [Na+]i, but the source of Na+ is not known.

METHODS AND RESULTS

Inhibitors of the voltage-gated Na+ channel were used to investigate the effect of Na+ channel blockade on hypoxic Na+ loading, Na(+)-dependent Ca2+ loading, and reoxygenation hypercontracture in isolated adult rat cardiac myocytes. Single electrically stimulated (0.2 Hz) cells were loaded with either SBFI (to index [Na+]i) or indo-1 (to index [Ca2+]i) and exposed to glucose-free hypoxia (PO2 < 0.02 mm Hg). Both [Na+]i and [Ca2+]i increased during hypoxia when cells became inexcitable following ATP-depletion contracture. The hypoxic rise in [Na+]i and [Ca2+]i was significantly attenuated by 1 mumol/L R 56865. Tetrodotoxin (60 mumol/L), a selective Na(+)-channel blocker, also markedly reduced the rise in [Ca2+]i during hypoxia and reoxygenation. Reoxygenation-induced cellular hypercontracture was reduced from 83% (45 of 54 cells) under control conditions to 12% (4 of 32) in the presence of R 56865 (P < .05). Lidocaine reduced hypercontracture dose dependently with 13% of cells hypercontracting in 100 mumol/L lidocaine, 42% in 50 mumol/L lidocaine, and 93% in 25 mumol/L lidocaine. The Na(+)-H+ exchange blocker, ethylisopropylamiloride (10 mumol/L) was also effective, limiting hypercontracture to 12%. R 56865, lidocaine, and ethylisopropylamiloride were also effective in preventing hypercontracture in normoxic myocytes induced by 75 mumol/L veratridine, an agent that impairs Na+ channel inactivation. Ethylisopropylamiloride prevented the veratridine-induced rise in [Ca2+]i without affecting Na(+)-Ca2+ exchange, suggesting that amiloride derivatives can reduce Ca2+ loading by blocking Na+ entry through Na+ channels, an action that may in part underlie their ability to prevent hypoxic Na+ and Ca2+ loading.

CONCLUSIONS

Na+ influx through the voltage-gated Na+ channel is an important route of hypoxic Na+ loading, Na(+)-dependent Ca2+ loading, and reoxygenation hypercontracture in isolated rat cardiac myocytes. Importantly, the Na+ channel appears to serve as a route for hypoxic Na+ influx after myocytes become inexcitable.
L-arginine reduces heart collagen accumulation in the diabetic db/db mouse.
Authors: Khaidar A , Marx M , Lubec B , Lubec G
Published: June 2012

BACKGROUND

Diabetic cardiomyopathy presents with significant collagen accumulation; decreased solubility, increased glucose-mediated abnormal cross-linking, free radical cross-linking, or glucose-induced increased transcription of collagen is incriminated. In a previous study, we reduced collagen accumulation in the kidneys of diabetic mice by treatment with oral arginine. This observation led us to examine the effect of arginine on cardial fibrosis.

METHODS AND RESULTS

Twenty-nine db/db spontaneously diabetic mice were used in the experiments. Sixteen were given L-arginine (free base, in tap water, 50 mg/kg body wt per day) for 4 months. At the end of the experiment, we determined total collagen content of total ventricular tissue, acid solubility, carboxymethyllysine, O-tyrosine, glutathione, blood glucose, and fructosamine as parameters for glycemic control. Heart collagen level was significantly (P = .0001) reduced in the experimental group (mean, 0.24 +/- 0.05) compared with the control group (mean, 0.49 +/- 0.10 mumol hydroxyproline per 100 mg heart tissue). Significantly more collagen could be eluted from heart samples of the experimental group (P = .02). Carboxymethyllysine and O-tyrosine did not differ when related to heart weight. Glutathione level was significantly higher in the untreated group (P = .003). Parameters of glycemic control did not differ between the groups.

CONCLUSIONS

Our findings clearly indicate that L-arginine reduced total heart collagen and increased acid solubility of heart collagen. Both findings are compatible with the cross-linking hypothesis. The data for carboxymethyllysine, O-tyrosine, and glutathione would rule out the glycoxidation hypothesis and, therefore, free radical cross-linking. The postulated mechanism of action is most likely the blocking of reactive carbonyl functions by L-arginine in analogy to aminoguanidine activity. Correlations of collagen with glycemic control, however, point to an association of glucose with collagen metabolism, a phenomenon documented in cell cultures at the transcriptional level.
Late enlargement of radiofrequency lesions in infant lambs. Implications for ablation procedures in small children.
Authors: Saul J P , Hulse J E , Papagiannis J , Van Praagh R , Walsh E P
Published: June 2012

BACKGROUND

Despite the current clinical use of radiofrequency (RF) catheter ablation in infants, the acute and late effects of RF lesion production in immature myocardium remain unknown. This study was specifically designed to investigate the pathology of RF lesions in developing sheep myocardium.

METHODS AND RESULTS

In study 1, RF lesions were made on the epicardial left ventricular surface of the beating heart in 15 sheep, 5 approximately 4 weeks of age (11.0 +/- 1.0 kg) and 10 approximately 8 weeks of age (23.8 +/- 3.4 kg), to assess the effects of RF application duration (10 to 90 seconds) and electrode tip temperature (45 degrees to 90 degrees C) on lesion size in immature myocardium. Lesion width and depth increased asymptotically with RF duration, to 7.0 +/- 0.7 and 4.8 +/- 1.0 mm at 90 seconds, respectively. The time to reach one-half lesion size was 6.5 seconds for width and 12.0 seconds for depth. Lesion width increased nearly linearly with tip temperature above 50 degrees C, but depth followed a sigmoid relation, with no increase above 80 degrees C. In study 2, RF lesions were made in all four cardiac chambers under fluoroscopic guidance in 19 infant sheep (10.9 +/- 1.4 kg). Lesion sizes and histological characteristics were assessed acutely (acute, n = 5), at 1.07 +/- 0.02 months (1 month, n = 5), and at 8.5 +/- 0.5 months (late, n = 9). Atrial and ventricular lesions but not atrioventricular groove lesions apparently increased in size during the follow-up period. Atrial lesions width increased from 5.3 +/- 0.5 to 8.7 +/- 0.7 mm at 1 month (164%) but did not increase further at late follow-up, while ventricular lesion width increased from 5.9 +/- 0.8 to 10.1 +/- 0.7 mm (171%) at late follow-up but was not significantly changed at 1 month. Histological evaluation revealed replacement of normal myocytes with fibrous and elastic tissue at 1 month and late follow-up in all locations but also demonstrated a poorly delineated border with multiple extensions of fibrous and elastic tissue into surrounding normal myocardium in late ventricular lesions.

CONCLUSIONS

RF lesion formation in immature sheep myocardium is similar to that in adult myocardium acutely but is associated with late lesion enlargement and fibrous tissue invasion of normal myocardium. These findings may have implications for clinical RF ablation procedures in infants.
Normal and abnormal consequences of apoptosis in the human heart. From postnatal morphogenesis to paroxysmal arrhythmias.
Authors: James T N
Published: June 2012

Apoptosis and necrosis are two distinctly different forms of cell death, and both occur in the human heart. In contrast to necrosis, apoptosis is not associated with inflammation for two reasons. First, the apoptotic cell does not swell or rupture before it is engulfed by either a macrophage or even a neighboring like cell. Second, the phagocytosis occurs with unusual rapidity. Apoptosis, also thought of as cell suicide, is a tidy way of removing cells no longer useful, in essence a form of selective deletion. These features make apoptosis a valuable component of morphogenesis, mediation of hormonal and immunologic responses, and the homeostatic balance between hypertrophy and atrophy or involution. In the human heart apoptosis has been found in the sinus node of patients with the long QT syndrome. It most likely participates in the important postnatal morphogenesis of the sinus node, AV node, and His bundle. Apoptosis may also participate in the genesis and pathophysiology of cardiomyopathy, paroxysmal arrhythmias, or conduction disturbances (some of which may be responsible for sudden death), focal fibromuscular dysplasia of small coronary arteries, hereditary medial degeneration of the tunica media of coronary arteries, and arrhythmogenic right ventricular dysplasia. The possible role apoptosis in numerous other changes in the human heart, among them the pathogenesis of atherosclerosis and mechanisms of aging in the myocardium, merits future investigation.
Adjunctive thrombolytic therapy during angioplasty for ischemic rest angina. Results of the TAUSA Trial. TAUSA Investigators. Thrombolysis and Angioplasty in Unstable Angina trial.
Authors: Ambrose J A , Almeida O D , Sharma S K , Torre S R , Marmur J D , Israel D H , Ratner D E , Weiss M B , Hjemdahl-Monsen C E , Myler R K
Published: June 2012

BACKGROUND

Acute closure is increased after angioplasty in unstable angina, and adjunctive intracoronary thrombolytic therapy has been used successfully to increase angiographic success. The role of prophylactic thrombolytic therapy during angioplasty in unstable angina is unknown.

METHODS AND RESULTS

Four hundred sixty-nine patients with ischemic rest pain with or without a recent (< 1 month) infarction were randomized in double-blind fashion to intracoronary urokinase or placebo. Randomization was carried out in two sequential phases. In phase I, 257 patients were randomized to 250,000 U of urokinase or placebo given in divided doses at the time of angioplasty. In phase II, 212 patients were randomized to 500,000 U of urokinase or placebo in divided doses. All patients were pretreated with aspirin, and activated clotting times were followed to maintain them at > 300 seconds during angioplasty. Angiographic end points of thrombus after angioplasty were insignificantly decreased by urokinase (30 [13.8%] versus 41 [18.0%] with placebo; P = NS). Acute closure, on the other hand, was increased with urokinase (23 [10.2%] versus 10 [4.3%] with placebo; P < .02). The difference in acute closure between urokinase and placebo was more striking at the higher dose of urokinase (P < .04) than in phase I at the lower urokinase dose (P = NS). Adverse in-hospital clinical end points (ischemia, infarction, or emergency coronary artery bypass surgery) were also increased with urokinase versus placebo (30 [12.9%] versus 15 [6.3%], respectively; P < .02). Angiographic and clinical end points were worse with urokinase in unstable angina without recent infarction than with angioplasty after a recent infarction.

CONCLUSIONS

Adjunctive urokinase given prophylactically during angioplasty for ischemic rest angina as administered in this trial is associated with adverse angiographic and clinical events. These detrimental effects may be related to hemorrhagic dissection, lack of intimal sealing, or procoagulant or platelet-activating effects of urokinase.
Weekly variation of acute myocardial infarction. Increased Monday risk in the working population.
Authors: Willich S N , Löwel H , Lewis M , Hörmann A , Arntz H R , Keil U
Published: June 2012

BACKGROUND

Seasonal and circadian variations in the occurrence of myocardial infarction and sudden cardiac death have been documented, suggesting that triggering factors may play a role in the causation of cardiac events. However, there are only sparse and conflicting data on the weekly distribution of the disorders.

METHODS AND RESULTS

To determine the weekly variation of acute myocardial infarction and sudden cardiac death, 5596 consecutive patients (71% men; age, 63 +/- 1 years) were analyzed in a regionally defined population (n = 330,000; age, 25 to 74 years) monitored from 1985 to 1990. The exact time of onset of symptoms was used to determine the day of the event. Patients with myocardial infarction (n = 2636) demonstrated a significant weekly variation (P < .01) with a peak on Monday, whereas patients with sudden cardiac death (n = 2960) were evenly distributed throughout the week. A similar weekly pattern was observed in subgroups of patients with myocardial infarction defined with respect to age, sex, cardiac risk factors, prior cardiac medication, and infarct characteristics. The working population demonstrated a weekly variation of myocardial infarction as opposed to the nonworking population, with a 33% increase in relative risk of disease onset on Monday (P < .05) and a trough on Sunday compared with the expected number of cases, if homogeneity was assumed.

CONCLUSIONS

The onset of acute myocardial infarction demonstrates a peak on Monday primarily in the working population. If this finding is confirmed in other communities, it may aid in identifying acute triggering events of myocardial infarction and perhaps in improving prevention of the disease.
Reduction in QT interval dispersion by successful thrombolytic therapy in acute myocardial infarction. TEAM-2 Study Investigators.
Authors: Moreno F L , Villanueva T , Karagounis L A , Anderson J L
Published: June 2012

BACKGROUND

QT dispersion (QTd, equals maximal minus minimal QT interval) on a standard ECG has been shown to reflect regional variations in ventricular repolarization and is significantly greater in patients with than in those without arrhythmic events.

METHODS AND RESULTS

To assess the effect of thrombolytic therapy on QTd, we studied 244 patients (196 men; mean age, 57 +/- 10 years) with acute myocardial infarction (AMI) who were treated with streptokinase (n = 115) or anistreplase (n = 129) at an average of 2.6 hours after symptom onset. Angiograms at 2.4 +/- 1 hours after thrombolytic therapy showed reperfusion (TIMI grade > or = 2) in 75% of patients. QT was measured in 10 +/- 2 leads at 9 +/- 5 days after AMI by using a computerized analysis program interfaced with a digitizer. QTd, QRSd, JT (QT minus QRS), and JT dispersion (JTd, equals maximal minus minimal JT interval) were calculated with a computer. There were significant differences in QTd (96 +/- 31, 88 +/- 25, 60 +/- 22, and 52 +/- 19 milliseconds; P < or = .0001) and in JTd (97 +/- 32, 88 +/- 31, 63 +/- 23, and 58 +/- 21 milliseconds; P = .0001) but not in QRSd (25 +/- 10, 22 +/- 7, 28 +/- 9, and 24 +/- 9 milliseconds; P = .24) among perfusion grades 0, 1, 2, and 3, respectively. Similar results were obtained comparing TIMI grades 0/1 with 2/3 and 0/1/2 with 3. Patients with left anterior descending (versus right and left circumflex) coronary artery occlusion showed significantly greater QTd (70 +/- 29 versus 59 +/- 27 milliseconds, P = .003) and JTd (74 +/- 30 versus 63 +/- 27 milliseconds, P = .004). Similarly, patients with anterior (versus inferior/lateral) AMI showed significantly greater QTd (69 +/- 30 versus 59 +/- 27 milliseconds, P = .006) and JTd (73 +/- 30 versus 63 +/- 27 milliseconds, P = .007). Results did not change when Bazett's QTc or JTc was substituted for QT or JT or when ANOVA included adjustments for age, sex, drug assignment, infarct site, infarct vessel, and number of measurable leads. On ANCOVA, the relation of QTd or JTd and perfusion grade was not influenced by heart rate.

CONCLUSIONS

Successful thrombolysis is associated with less QTd and JTd in post-AMI patients. The results are equally significant when either QT or JT is used for analysis. These data support the hypothesis that QTd after AMI depends on reperfusion status as well as infarct site and size. Reduction in QTd and its corresponding risk of ventricular arrhythmia may be mechanisms of benefit of thrombolytic therapy.
Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only.
Authors: Brogi E , Wu T , Namiki A , Isner J M
Published: June 2012

BACKGROUND

Hypoxia and indirect angiogenic factors may stimulate angiogenesis via induction of endothelial cell mitogen(s). To evaluate this hypothesis, we investigated whether low oxygen tension or cytokines known to promote neovascularization in vivo could modulate the expression of either vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) in human vascular smooth muscle cells (SMCs).

METHODS AND RESULTS

SMCs were treated with platelet-derived growth factor BB (PDGF-BB) or transforming growth factor-beta 1 (TGF-beta 1) or exposed to low oxygen tension in serum-free medium. Northern analysis detected low basal levels of VEGF and bFGF mRNA in extracts of unstimulated SMCs. However, both VEGF and bFGF transcripts increased after administration of PDGF-BB (10 or 20 ng/mL) or TGF-beta 1 (0.1 to 10 ng/mL). Hypoxia was a potent stimulus for VEGF gene expression but had no apparent effect on bFGF steady-state mRNA levels.

CONCLUSIONS

These results indicate that certain indirect angiogenic cytokines, such as PDGF-BB or TGF-beta 1, may act via induction of bFGF and VEGF gene expression in cells resident near endothelial cells in vivo. Hypoxia constitutes a potent stimulus for VEGF gene expresion but does not regulate bFGF under the same experimental conditions.
Effects of L-arginine on impaired acetylcholine-induced and ischemic vasodilation of the forearm in patients with heart failure.
Authors: Hirooka Y , Imaizumi T , Tagawa T , Shiramoto M , Endo T , Ando S , Takeshita A
Published: June 2012

BACKGROUND

Endothelium-dependent vasodilation in response to acetylcholine (ACh) and ischemic vasodilation during reactive hyperemia are attenuated in the forearm of patients with heart failure (HF). It has been shown that L-arginine augments endothelium-dependent vasodilation in healthy subjects. Thus, the aim of the present study was to determine if L-arginine improves endothelium-dependent and ischemic vasodilation in the forearm in HF.

METHODS AND RESULTS

Forearm blood flow was measured by a strain-gauge plethysmograph in 20 patients with HF and in 24 age-matched control subjects (C). Resting forearm vascular resistance (FVR) was significantly higher in HF than in C (37 +/- 4 versus 22 +/- 2 U, P < .01). Intra-arterial infusions of ACh or sodium nitroprusside (SNP) at graded doses progressively decreased FVR in HF as well as in C. The magnitude of ACh-induced vasodilation was attenuated in HF (P < .01), whereas SNP-induced vasodilation was similar between the two groups. The minimal FVR during reactive hyperemia after 10 minutes of arterial occlusion was significantly higher in HF (n = 12) than in C (n = 12) (3.2 +/- 0.4 versus 2.1 +/- 0.1 U, P < .05). L-Arginine significantly augmented maximal vasodilation evoked with ACh and decreased minimal FVR during reactive hyperemia in HF (P < .01) but not in C. L-Arginine did not affect SNP-induced vasodilation in HF or C.

CONCLUSIONS

Our results suggest that defective endothelial function may contribute to impaired ischemic vasodilator capacity in HF.
Acute vascular effects of estrogen in postmenopausal women.
Authors: Gilligan D M , Badar D M , Panza J A , Quyyumi A A , Cannon R O
Published: June 2012

BACKGROUND

Although hormone replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanisms that mediate this apparent benefit are unclear. Because improvement in vasomotor function may represent one of the beneficial effects of estrogen administration, we investigated the acute effects of physiological levels of estrogen on the vascular responses of estrogen-deficient postmenopausal women.

METHODS AND RESULTS

The study included 40 postmenopausal women 60 +/- 8 years old (mean +/- SD), 20 of whom had one or more conditions associated with vascular dysfunction (hypertension, hypercholesterolemia, diabetes, or coronary artery disease). The forearm vascular responses to the endothelium-dependent vasodilator acetylcholine were studied before and during infusion of 17 beta-estradiol into the ipsilateral brachial artery. In 31 subjects, the effect of estradiol on the responses to the endothelium-independent vasodilator sodium nitroprusside was also studied. Women with risk factors for vascular dysfunction had significantly reduced vasodilator responses to acetylcholine (P = .01) and to sodium nitroprusside (P < .001) compared with healthy subjects. Intra-arterial infusion of 17 beta-estradiol increased the forearm venous estradiol concentration from 16 +/- 10 to 318 +/- 188 pg/mL, levels typical of reproductive-age women at midcycle, but caused no vasodilation. However, estradiol potentiated the forearm vasodilation induced by acetylcholine by 18 +/- 30% (P < .001) in women with risk factors for vascular dysfunction and by 14 +/- 23% (P = .03) in healthy women. Estradiol also potentiated the forearm vasodilation induced by sodium nitroprusside in women with risk factors for vascular dysfunction by 14 +/- 21% (P < .001) but not in healthy women.

CONCLUSIONS

Physiological levels of 17 beta-estradiol selectively potentiate endothelium-dependent vasodilation in healthy postmenopausal women and potentiate both endothelium-dependent and endothelium-independent vasodilation in post-menopausal women with risk factors for atherosclerosis and evidence of impaired vascular function. These vascular effects may be partly responsible for the long-term benefit of estrogen therapy on cardiovascular events in postmenopausal women.
Plasma arteriovenous cGMP difference as a useful indicator of nitrate tolerance in patients with heart failure.
Authors: Tsutamoto T , Kinoshita M , Ohbayashi Y , Wada A , Maeda Y , Adachi T
Published: June 2012

BACKGROUND

The present study was performed to evaluate the effects of nitroglycerin (GTN) on plasma arteriovenous cGMP production and to compare its hemodynamic effects in patients with congestive heart failure (CHF). We also estimated the potential clinical value of plasma arteriovenous cGMP production as an indicator of nitrate tolerance.

METHODS AND RESULTS

Plasma arterial and venous cGMP levels, atrial natriuretic peptide level, and hemodynamic parameters were measured before and after GTN infusion in 14 patients with CHF. Although the plasma levels of arterial cGMP and atrial natriuretic peptide decreased immediately after GTN, the plasma level of venous cGMP did not change. GTN infusion caused a dose-dependent increase in plasma arteriovenous cGMP production, and there was a positive correlation between the decrease of pulmonary capillary wedge pressure and the increase of plasma arteriovenous cGMP production immediately after GTN. Hemodynamic tolerance was observed after both 12 and 24 hours, when plasma arteriovenous GMP production was also attenuated.

CONCLUSIONS

These findings indicate that the plasma arteriovenous cGMP difference is a clinical indicator of vasodilatory action of GTN and a useful indicator of nitrate tolerance in patients with CHF.