bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure-dependent dynamic mechanical behavior of fibrous caps from human atherosclerotic plaques.
Authors: Lee R T , Grodzinsky A J , Frank E H , Kamm R D , Schoen F J
Published: June 2012

BACKGROUND

Although thrombosis associated with a fissured atherosclerotic plaque is believed to be the most common cause of acute coronary syndromes, the underlying factors that trigger plaque rupture are currently unknown. However, the mechanical behavior of the plaque is probably of critical importance.

METHODS AND RESULTS

To test the hypothesis that the mechanical properties of a plaque are dependent on its composition and, in particular, that the stiffness of fibrous caps changes within the range of frequencies carried by a physiological pressure wave, the stress-strain relation was studied in 27 fibrous caps and related to the underlying histological structure of the fibrous cap. Fibrous caps were obtained during 14 autopsies from the abdominal aorta and were classified by histological examination as cellular (n = 7), hypocellular (n = 9), or calcified (n = 11). Hypocellular fibrous caps were 1-2 times stiffer than cellular caps (p less than 0.005), and calcified caps were 4-5 times stiffer than cellular caps (p less than 0.005). All 27 fibrous caps demonstrated an increase in stiffness with increasing frequencies of stress ranging from 0.05 to 10 Hz; the increase in stiffness was similar in all three histological classes.

CONCLUSIONS

We conclude that the stiffness of fibrous caps from human atherosclerotic plaques is related to the underlying histological structure and that the stiffness increases with frequency in the range of physiological heart rates. The protective benefit of beta-adrenergic receptor blocking agents in coronary artery disease may, in part, be related to the frequency dependence of atherosclerotic plaque stiffness.
Coronary stenting with a new, radiopaque, balloon-expandable endoprosthesis in pigs.
Authors: van der Giessen W J , Serruys P W , van Beusekom H M , van Woerkens L J , van Loon H , Soei L K , Strauss B H , Beatt K J , Verdouw P D
Published: June 2012

BACKGROUND

Intracoronary stents may be effective when used as "bail-out" devices for acute complications after percutaneous transluminal coronary angioplasty. Furthermore, preliminary reports have demonstrated some promising results with stents with regard to the reduction of restenosis. Several stent devices are available for preclinical and clinical evaluation. The use of these stainless-steel stents has been limited by poor visibility during fluoroscopy and thrombogenicity during the first days to weeks after implantation. We therefore investigated the immediate and short-term effects on arterial patency of a new, radiopaque, balloon-expandable coil stent in normal coronary arteries of pigs.

METHODS AND RESULTS

In 10 animals, a stent was placed in two of the three epicardial coronary arteries. During the implantation procedure, the animals received heparin; after the procedure, no antithrombotic drugs were administered. After 1 week (five animals and 10 stents) or 4 weeks (five animals and 10 stents), repeat angiography was performed, followed by pressure-fixation of the coronary arteries for light and electron microscopic examination. Angiographic analysis revealed that all stented coronary segments were patent and without signs of intraluminal defects. Scanning electron microscopy showed complete endothelial covering of all stents within 7 days. Light microscopy showed a reduced tunica media locally under the stent wires, which resulted from exerted pressure. The neointima on top of the stent wires measured 56 microns (range, 42-88 microns) after 1 week and 139 microns (range, 84-250 microns) after 4 weeks.

CONCLUSIONS

Results from this study show that this radiopaque endoprosthesis can be safely placed in normal coronary arteries of pigs. After 4 weeks, all stents were patent and there was no need for additional antithrombotic treatment, whereas neointimal proliferation was limited.
Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system.
Authors: Weber K T , Brilla C G
Published: June 2012

Left ventricular hypertrophy (LVH) is the major risk factor associated with myocardial failure. An explanation for why a presumptive adaptation such as LVH would prove pathological has been elusive. Insights into the impairment in contractility of the hypertrophied myocardium have been sought in the biochemistry of cardiac myocyte contraction. Equally compelling is a consideration of abnormalities in myocardial structure that impair organ contractile function while preserving myocyte contractility. For example, in the LVH that accompanies hypertension, the extracellular space is frequently the site of an abnormal accumulation of fibrillar collagen. This reactive and progressive interstitial and perivascular fibrosis accounts for abnormal myocardial stiffness and ultimately ventricular dysfunction and is likely a result of cardiac fibroblast growth and enhanced collagen synthesis. The disproportionate involvement of this nonmyocyte cell, however, is not a uniform accompaniment to myocyte hypertrophy and LVH, suggesting that the growth of myocyte and nonmyocyte cells is independent of each other. This has now been demonstrated in in vivo studies of experimental hypertension in which the abnormal fibrous tissue response was found in the hypertensive, hypertrophied left ventricle as well as in the normotensive, nonhypertrophied right ventricle. These findings further suggest that a circulating substance that gained access to the common coronary circulation of the ventricles was involved. This hypothesis has been tested in various animal models in which plasma concentrations of angiotensin II and aldosterone were varied. Based on morphometric and morphological findings, it can be concluded that arterial hypertension (i.e., an elevation in coronary perfusion pressure) together with elevated circulating aldosterone are associated with cardiac fibroblast involvement and the resultant heterogeneity in tissue structure. Nonmyocyte cells of the cardiac interstitium represent an important determinant of pathological LVH. The mechanisms that invoke short- (e.g., collagen metabolism) and long-term (e.g., mitosis) responses of cardiac fibroblasts require further investigation and integration of in vitro with in vivo studies. The stage is set, however, to prevent pathological LVH resulting from myocardial fibrosis as well as to reverse it.
Limb vascular responsiveness to beta-adrenergic receptor stimulation in patients with congestive heart failure.
Authors: Creager M A , Quigg R J , Ren C J , Roddy M A , Colucci W S
Published: June 2012

BACKGROUND

In patients with congestive heart failure, the chronotropic and inotropic responses to beta-adrenergic agonists are reduced. It is not known whether desensitization of peripheral beta-adrenoceptors accounts for impaired limb vasodilation in these patients. Accordingly, we studied 14 normal subjects and 13 age-matched patients with congestive heart failure.

METHODS AND RESULTS

To distinguish vasodilation mediated by beta-adrenoceptors and adenylate cyclase from that mediated by stimulation of guanylate cyclase, each subject received intrabrachial artery infusions of isoproterenol (1-100 ng/min) and sodium nitroprusside (0.3-10 micrograms/min), respectively. Forearm blood flow was determined by venous occlusion plethysmography. Maximal vasodilative potential, determined during reactive hyperemia, was reduced in the patients with congestive heart failure. The maximal forearm blood flow response to isoproterenol was comparable in patients with heart failure and in normal subjects (8.0 +/- 1.1 versus 9.2 +/- 1.2 ml/100 ml of tissue/min, respectively, p = NS). Furthermore, the dose-response relation to isoproterenol was similar in both groups. Likewise, the forearm vasodilative response to sodium nitroprusside was preserved in the heart failure group. Plasma concentration of norepinephrine was higher in the patients with heart failure (436 +/- 34 versus 201 +/- 74 pg/ml, p less than 0.01). When both groups were considered, there was no correlation between norepinephrine levels and the maximal forearm blood flow response to isoproterenol (r = 0.10, p = NS).

CONCLUSIONS

We conclude that beta-adrenoceptor desensitization does not occur in the limb vessels of patients with congestive heart failure.
Effect of exercise intensity and duration on regional function during and after exercise-induced ischemia.
Authors: Homans D C , Laxson D D , Sublett E , Pavek T , Crampton M
Published: June 2012

BACKGROUND

Transient reversible myocardial dysfunction has been documented after episodes of exercise-induced ischemia. This study was undertaken to determine whether the duration or intensity of exercise affects the severity of postischemic dysfunction in this setting.

METHODS AND RESULTS

Ten dogs were instrumented with ultrasonic microcrystals for measurement of wall thickening, with circumflex coronary artery flow probes, and with hydraulic occluders. Dogs performed low-intensity exercise, which was sufficient to increase coronary perfusion 50% above control, and high-intensity exercise, which was sufficient to double coronary blood flow. To investigate the effects of exercise intensity on postischemic dysfunction, we had dogs perform high-intensity exercise for 5 minutes in the presence of a stenosis. On the alternate day, dogs performed low-intensity exercise for 10 minutes in the presence of a stenosis. These two protocols provide equivalent coronary flow debts. Mean transmural blood flow during high-intensity exercise without stenosis (2.61 +/- 0.54 ml/min/g) was significantly higher than that during low-intensity exercise (1.74 +/- 0.61 ml/min/g, p less than 0.002). During high-intensity exercise with coronary artery stenosis, subendocardial blood flow was significantly lower than that during low-intensity exercise with stenosis (0.64 +/- 0.40 versus 1.08 +/- 0.28 ml/min/g, p less than 0.02). This difference in subendocardial perfusion was associated with greater degrees of regional dysfunction during exercise (circumflex wall thickening was 44 +/- 23% of control for high-intensity exercise versus 60 +/- 18% of control for low-intensity exercise, p less than 0.01). In addition, from 10 to 30 minutes after exercise, wall thickening in myocardium perfused by the circumflex coronary artery remained significantly lower after high-intensity exercise than that after low-intensity exercise. To assess the effects of exercise duration on the severity of postischemic dysfunction, we had dogs perform low-intensity exercise in the presence of a coronary stenosis for 10 minutes and low-intensity exercise for only 5 minutes on alternate days. Systolic wall thickening was significantly lower after low-intensity exercise for 10 minutes than after low-intensity exercise for 5 minutes.

CONCLUSIONS

High-intensity exercise results in greater degrees of subendocardial hypoperfusion and greater degrees of regional dysfunction both during and after exercise-induced ischemia than does low-intensity exercise. Second, exercise duration also exerts an effect on the severity of postischemic dysfunction, although the magnitude of this effect is less important than the effect of exercise intensity.
Electrophysiological effects of left ventricular hypertrophy. Effect of calcium and potassium channel blockade.
Authors: Kowey P R , Friechling T D , Sewter J , Wu Y , Sokil A , Paul J , Nocella J
Published: June 2012

BACKGROUND

To define the arrhythmogenic effects of left ventricular hypertrophy (LVH) in the intact heart, we carried out a detailed electrophysiological assessment in our previously validated feline aortic-banding model and then tested the effects of agents that blocked either the slow inward calcium or voltage-dependent potassium channel.

METHODS AND RESULTS

We measured intraventricular and interventricular conduction times, excitability thresholds, ventricular effective refractory periods, and monophasic action potential duration at several sites in cats with LVH as well as in concurrent control (sham-operated) cats. In addition, we assessed vulnerability to ventricular arrhythmia using direct measurement of ventricular fibrillation (VF) thresholds and by standard techniques of programmed stimulation. Despite finding no difference between LVH and sham-operated cats in mean values for several electrophysiological parameters, the former group was significantly more vulnerable to VF, with more spontaneous VF and lower VF thresholds. Compared with the sham controls, LVH cats also had a greater dispersion of effective refractory period (35 +/- 11 versus 12 +/- 4 msec, p less than 0.01) and monophasic action potential duration at 90% repolarization (69 +/- 25 versus 39 +/- 7 msec, p less than 0.02). Verapamil had no significant effect on these electrophysiological parameters, nor did it affect VF threshold. However, risotilide, an inhibitor of the voltage-dependent potassium channel, narrowed dispersion of the effective refractory period and monophasic action potential duration concomitant with a marked reduction in ventricular vulnerability.

CONCLUSIONS

LVH has a pronounced effect on dispersion of refractoriness and repolarization and renders the ventricle more vulnerable to fibrillation. Blockade of the voltage-dependent potassium channel, but not the slow inward calcium channel, narrows the dispersion of recovery of excitability and protects against VF.
Current role of catheter ablative procedures in patients with cardiac arrhythmias. A report for health professionals from the Subcommittee on Electrocardiography and Electrophysiology, American Heart Association.
Authors: Scheinman M M , Laks M M , DiMarco J , Plumb V
Published: June 2012

Catheter ablative techniques have assumed an increasingly important role in the treatment of patients with drug-refractory cardiac arrhythmias. Catheter ablation of the AV junction is considered the procedure of choice for management of patients without bypass tracts with drug-resistant supraventricular arrhythmias. Catheter techniques have been used with increasing frequency in attempts to ablate accessory AV tracts. These techniques currently appear to be less effective than surgical techniques but involve less morbidity and expense. In some centers, accessory pathway ablation using catheter techniques is the procedure of first choice in selected patients with drug-refractory tachycardia mediated by an accessory pathway. Catheter ablation of ventricular tachycardia should be reserved for patients with mappable ventricular tachycardia who are not candidates for cardiac electrosurgery or insertion of an automatic defibrillator. The development of more flexible catheters and more manageable energy delivery systems holds promise for more effective catheter techniques.
Prospective evaluation of the risk of bacteremia associated with transesophageal echocardiography.
Authors: Steckelberg J M , Khandheria B K , Anhalt J P , Ballard D J , Seward J B , Click R L , Wilson W R
Published: June 2012

BACKGROUND

Transient bacteremia may lead to endocarditis in patients with significant valvular lesions.

METHODS AND RESULTS

Because transesophageal echocardiography selects a patient population with a high prevalence of valvular lesions, we prospectively evaluated the risk of transient bacteremia associated with transesophageal echocardiography in 49 patients. Blood cultures were obtained immediately before transesophageal echocardiography and at 5, 10, and 20 minutes after the start of the procedure. For each culture, 30 ml venous blood was obtained and 10 ml was inoculated into each of an Isolator tube, Septi-chek bottle, and a nonvented Trypticase soy broth bottle. Broth cultures were incubated for 14 days. Blood from the Isolator tube was plated onto appropriate media for recovery of bacteria and fungi. Two patients were excluded from analysis because the final two sets of blood cultures could not be obtained. Among the remaining 47 study patients, two preprocedure control blood cultures were positive, and two of 141 subsequent cultures were positive. All isolates were considered contaminants. Thus, we found no significant bacteremia due to pathogenic oral flora during transesophageal echocardiography (0%; 95% CI, 0.0-7.5%).

CONCLUSIONS

Although recommendations for antimicrobial prophylaxis for transesophageal echocardiography should be individualized for each patient, many patients may not require antimicrobial prophylaxis.
Comparative effects of pacing-induced and balloon coronary occlusion ischemia on left ventricular diastolic function in man.
Authors: Bronzwaer J G , de Bruyne B , Ascoop C A , Paulus W J
Published: June 2012

BACKGROUND

Effects of pacing-induced and coronary occlusion myocardial ischemia on left ventricular (LV) function have been compared only in anesthetized dogs. Diastolic properties of the same LV anterior wall segment were therefore compared in 12 patients with single-vessel proximal left anterior descending coronary artery stenosis at rest, immediately after 7 +/- 1.2 minutes of pacing, and at the end of a 1-minute balloon occlusion of coronary angioplasty (CO).

METHODS AND RESULTS

Shifts of the diastolic LV pressure-length relation, derived from simultaneous tip-micromanometer LV pressure recordings and digital subtraction LV angiograms, were used as an index of regional diastolic LV distensibility of the anterior wall segment. Immediately after pacing, LV end-diastolic pressure rose from 13.5 +/- 3.5 to 23.8 +/- 7.0 mm Hg (p less than 0.01 versus at rest) without a significant change of the LV end-diastolic volume index (83.1 +/- 18.9 versus 88.4 +/- 16.5 ml/m2), percentage systolic shortening (%SS) of the ischemic segment fell from 40.1 +/- 10.6% to 25.2 +/- 8.6% (p less than 0.01), and the diastolic LV pressure-radial length (P-RL) plot of the ischemic segment was shifted upward by 7.1 +/- 5.0 mm Hg for portions of the plot that overlapped with the diastolic LV P-RL plot at rest. At the end of CO, LV end-diastolic pressure rose to 20.8 +/- 7.8 mm Hg (p less than 0.01 versus at rest) and the LV end-diastolic volume index rose to 95.6 +/- 16.3 ml/m2 (p less than 0.05 versus at rest, p less than 0.05 versus after pacing). Ejection fraction and %SS of the ischemic segment fell respectively from 76.6 +/- 6.8% to 46.6 +/- 11.4% (p less than 0.01 versus at rest, p less than 0.01 versus after pacing) and from 40.1 +/- 10.6% to 6.4 +/- 8.6% (p less than 0.01 versus at rest, p less than 0.01 versus after pacing). The diastolic LV P-RL plot of the ischemic segment was shifted upward by 3.1 +/- 2.3 mm Hg for portions of the plot that overlapped with the diastolic LV P-RL plot at rest. This upward shift at the end of CO was significantly smaller (p less than 0.05) than that immediately after pacing. At the end of CO, a correlation (p less than 0.03) was observed for the ischemic segment between %SS and upward shift of the diastolic LV P-RL plot.

CONCLUSIONS

The upward shift of the diastolic LV P-RL plot, which was used as an index of decreased regional diastolic LV distensibility, was larger immediately after pacing than at the end of CO. Persistent systolic shortening of ischemic myocardium seems to be a prerequisite for a decrease in diastolic distensibility of the ischemic segment because of the higher %SS of the ischemic segment immediately after pacing, and because of the correlation at the end of CO between the upward shift of the diastolic LV P-RL plot and %SS of the ischemic segment.
Assessment of left atrial appendage function by transesophageal echocardiography. Implications for the development of thrombus.
Authors: Pollick C , Taylor D
Published: June 2012

BACKGROUND

The predilection of the left atrial appendage (LAA) for thrombus formation has long been known.

METHODS AND RESULTS

We prospectively studied the two-dimensional echocardiographic and Doppler patterns of LAA function in 82 patients by transesophageal echocardiography. In the 63 patients in sinus rhythm, LAA area was measured during LAA diastole at the onset of the electrocardiographic (ECG) P wave (LAAmax) and after LAA systole at the ECG R wave (LAAmin) and LAA ejection fraction was calculated as (LAAmax-LAAmin)/LAAmax; peak Doppler velocity was recorded from the LAA outlet. The 58 patients in sinus rhythm without LAA thrombus were grouped according to left atrial size on transthoracic echocardiography; 39 patients had a left atrial size of less than 40 mm (group 1) and 19 had a left atrial size of 40 mm or greater (group 2). Five patients in sinus rhythm had LAA thrombus. In the 19 patients with atrial fibrillation or flutter LAAmax was measured independent of the ECG; three of these patients had LAA spontaneous contrast, four had thrombus, and one had both. Patients in sinus rhythm without LAA thrombus demonstrated a characteristic pattern of a contractile LAA apex and a noncontractile base with color flow and pulsed Doppler evidence of LAA emptying that coincided with the P wave. Patients in sinus rhythm with LAA thrombus had a mean +/- SD LAAmax (8.0 +/- 1.5 cm2) larger than that in group 1 (5.0 +/- 1.9 cm2) (p less than 0.01) but not group 2 (6.7 +/- 3.1 cm2), LAAmin (6.5 +/- 1.0 cm2) larger than that in both group 1 (2.3 +/- 1.5 cm2) and group 2 (4.2 +/- 2.7 cm2) (p less than 0.01), and LAA ejection fraction (17 +/- 11%) and LAA velocity (0.24 +/- 0.10 m/sec) less than those in both group 1 (55 +/- 21% and 0.48 +/- 0.24 m/sec, respectively) and group 2 (45 +/- 27% and 0.46 +/- 0.24 m/sec, respectively) (p less than 0.01). Patients with atrial fibrillation or flutter with LAA spontaneous contrast and/or thrombus had LAAmax (10.4 +/- 6.6 cm2) greater than that in patients with atrial fibrillation or flutter without LAA contrast and/or thrombus (6.8 +/- 3.0 cm2) (p less than 0.05). The LAA appeared as a static pouch in seven of eight of the former compared with in two of 11 of the latter. When attempted, Doppler demonstrated a recognizable fibrillatory LAA outflow velocity pattern in none of three in the former versus four of seven in the latter group.

CONCLUSIONS

We conclude that the LAA has a characteristic pattern of emptying in sinus rhythm. LAA thrombus formation in sinus rhythm and atrial fibrillation is associated with both poor LAA contraction and LAA dilation.
Effectiveness of recombinant desulphatohirudin in reducing restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits.
Authors: Sarembock I J , Gertz S D , Gimple L W , Owen R M , Powers E R , Roberts W C
Published: June 2012

BACKGROUND

The effectiveness of balloon angioplasty is limited by a restenosis rate of approximately 30%. Recombinant desulphatohirudin (r-hirudin [CGP 39393]) has been found to be highly effective in preventing acute platelet-rich thrombosis after deep arterial injury as compared with heparin.

METHODS AND RESULTS

This study evaluated the effect of intravenous r-hirudin, a selective inhibitor of thrombin, on restenosis after balloon angioplasty in 29 rabbits. Focal femoral atherosclerosis was induced by air desiccation endothelial injury followed by a 2% cholesterol diet for 1 month. At angioplasty (2.5-mm balloon with three 60-second, 10-atm inflations 60 seconds apart), the rabbits received heparin (150 units/kg bolus, n = 16) or r-hirudin (1 mg/kg bolus followed by infusions of 1 mg/kg for the first hour and 0.5 mg/kg for the second hour, n = 13). Angiograms performed before and after angioplasty and before death were analyzed quantitatively by a blinded observer. Rabbits were killed 2 hours (n = 14) or 28 days (n = 15) after angioplasty. Femoral arteries were fixed in situ by perfusion of 10% formaldehyde at 100 mm Hg. The mean luminal diameter of the arteries with successful angioplasty (greater than or equal to 20% increase in luminal diameter) in rabbits treated with heparin (n = 8 arteries) increased from 1.18 +/- 0.29 mm before angioplasty to 1.86 +/- 0.24 mm immediately after angioplasty (p less than 0.001) and decreased to 0.94 +/- 0.69 mm (p = 0.0004) at 28 days after angioplasty. In rabbits treated with r-hirudin (n = 11 arteries), the mean luminal diameter increased from 1.14 +/- 0.17 mm before angioplasty to 1.68 +/- 0.20 mm immediately after angioplasty (p less than 0.001) and decreased to 1.37 +/- 0.47 mm (p = 0.01) at 28 days after angioplasty. The mean reduction in luminal diameter by angiography was less in the r-hirudin-treated group than in the heparin-treated group (0.30 +/- 0.33 versus 0.92 +/- 0.61 mm, p = 0.01). Blinded planimetric analysis of stained histological sections of the femoral arteries also showed less cross-sectional area narrowing by plaque in rabbits treated with r-hirudin compared with those treated with heparin (22 +/- 16% verus 48 +/- 29%, p = 0.01). Both groups had similar numbers of arteries with histological evidence of balloon-induced plaque tear (12 of 13 versus 13 of 15).

CONCLUSIONS

Rabbits receiving r-hirudin at the time of experimental balloon angioplasty had significantly less restenosis by angiography and by quantitative histopathology than rabbits receiving heparin.
Chronic beta-adrenoceptor blockade prevents the development of beta-adrenergic subsensitivity in experimental right-sided congestive heart failure in dogs.
Authors: Liang C S , Frantz R P , Suematsu M , Sakamoto S , Sullebarger J T , Fan T M , Guthinger L
Published: June 2012

BACKGROUND

The reductions of myocardial beta-adrenergic receptor density and responsiveness to catecholamines in congestive heart failure are associated with excessive sympathetic stimulation. The purpose of this study was to determine whether the myocardial changes could be prevented by beta-receptor blockade.

METHODS AND RESULTS

We administered the oral beta-receptor blocking agent nadolol (40 mg/day) to dogs during an early stage of experimental right heart failure and to sham-operated dogs for 5 weeks. Animals receiving no nadolol were studied concurrently. Nadolol treatment did not prevent right ventricular hypertrophy or elevated concentrations of plasma norepinephrine that occurred in right heart failure, nor did it affect the decrease in myocardial norepinephrine content and norepinephrine uptake activity, suggesting that the hemodynamic stress imposed on the right ventricle of dogs with right heart failure was similar regardless of the presence or absence of beta-receptor blockade. Resting heart rate, right atrial pressure, aortic pressure, cardiac output, right ventricular dP/dt, and left ventricular dP/dt and dP/dt/P measured 5 days after discontinuation of nadolol did not differ significantly from those without nadolol treatment in either right heart failure or sham-operated animals. Sham-operated dogs also showed no changes in myocardial beta-receptor or adenylate cyclase activity after nadolol treatment. However, nadolol treatment prevented the reduction of myocardial beta-receptor density and attenuated the decrease in the cardiac beta-adrenergic sensitivity that occurred in right heart failure.

CONCLUSIONS

Excessive sympathetic stimulation may play an important role in the development of beta-receptor downregulation and beta-adrenergic subsensitivity in right heart failure.
A new method for assessment of cultured cardiac myocyte contractility detects immune factor-mediated inhibition of beta-adrenergic responses.
Authors: Gulick T , Pieper S J , Murphy M A , Lange L G , Schreiner G F
Published: June 2012

BACKGROUND

Potentially reversible congestive heart failure accompanies disease states associated with an immune cell myocardial infiltrate such as cardiac allograft rejection and inflammatory myocarditis. We therefore examined the hypothesis that immune cells can produce noncytotoxic alterations in cardiac function.

METHODS AND RESULTS

A novel system to evaluate cultured cardiac myocyte contractility was developed using neonatal rat cardiocytes grown on human amniotic membrane segments. Spontaneous synchronous cell beating produced macroscopic distortion of these membranes. Movement of free-floating membranes anchored within a perfusion chamber was visualized under low-power microscopy and measured from recordings of the rhythmic displacement of membrane-adherent markers. Additions of graded concentrations of isoproterenol to the perfusate produced up to threefold increases in the initial contractile phase velocity (contractile index), with an EC50 of 10(-7) M. When the extracellular Ca2+ concentration was increased from 0.9 to 3.6 mM, 2.43-fold increases in this index occurred. Myocytes incubated for 72 hours in the presence of dilutions of medium conditioned by activated rat splenic macrophages and lymphocytes exhibited an isoproterenol contractile index inhibited by 62% compared with control cells. In contrast, responses of supernatant-exposed and control cells to increased extracellular Ca2+ concentrations were not significantly different. Parallel studies of increases in myocyte intracellular adenosine 3':5'-cyclic monophosphate concentrations in response to isoproterenol stimulation demonstrated correlative inhibition that was specific for exposure to medium conditioned by immune cells.

CONCLUSION

Thus, a new method of in vitro cardiac contractility assessment that has significant advantages over existing systems has been developed and characterized. This new method has enabled description of an inhibitor of cardiac contractile function produced by activated immune cells.
Concurrent hydralazine administration prevents nitroglycerin-induced hemodynamic tolerance in experimental heart failure.
Authors: Bauer J A , Fung H L
Published: June 2012

BACKGROUND

Organic nitrates such as nitroglycerin and isosorbide dinitrate are useful in the treatment of congestive heart failure (CHF), but tolerance develops rapidly during continuous administration. Because combination therapy of nitrate and hydralazine has been shown to provide both short- and long-term benefit but nitrate alone produces hemodynamic tolerance, we questioned whether hydralazine can preserve the favorable preload effects of nitroglycerin.

METHODS AND RESULTS

Using an in vivo model of nitroglycerin tolerance in the CHF rat, we examined the effects of hydralazine bolus dosing during continuous nitroglycerin infusion. Continuous infusion of nitroglycerin alone (10 micrograms/min) produced initial reductions in left ventricular end-diastolic pressure of 40-50%, which returned to baseline by 8 hours (tolerance development). Coadministration of hydralazine (2 x 0.1 mg) maintained the effects of nitroglycerin infusion on left ventricular end-diastolic pressure (45% reduction at 10 hours). This hydralazine dose alone reduced left ventricular peak systolic pressure by approximately 12 +/- 3% but had no effect on left ventricular end-diastolic pressure. Hydralazine dosing did not affect steady-state plasma concentrations of nitroglycerin or metabolites, and hydralazine was unable to prevent nitroglycerin tolerance induced in vitro.

CONCLUSIONS

The beneficial interaction of hydralazine on the preload effects of nitroglycerin may explain the long-term clinical efficacy of hydralazine/nitrate combination in CHF. Our results also suggest that the mechanism of in vivo nitrate tolerance in CHF may be systemic rather than vascular in origin.
Arrhythmogenic effects of graded coronary blood flow reductions superimposed on prior myocardial infarction in dogs.
Authors: Furukawa T , Moroe K , Mayrovitz H N , Sampsell R , Furukawa N , Myerburg R J
Published: June 2012

BACKGROUND

We studied arrhythmogenesis and its underlying pathophysiology during graded reductions of coronary blood flow, superimposed on prior myocardial infarction to test the hypothesis that spontaneous ventricular fibrillation and induced ventricular tachycardia are dependent on different patterns of coronary flow reduction in hearts with prior myocardial infarction.

METHODS AND RESULTS

In 10 sham-operated dogs (control group) and 24 dogs with 3-week-old experimental apical myocardial infarction, the left circumflex coronary artery was constricted to produce four grades of flow reduction: 25%, 50%, 75%, and 100%. Among the sham-operated control animals, only one of 10 (10%) developed spontaneous ventricular fibrillation and only two of nine (22%) were inducible into sustained ventricular tachycardia during 100% circumflex coronary artery flow reduction. No spontaneous ventricular fibrillation or inducible ventricular tachycardia occurred with lesser grades (25%, 50%, or 75%) of flow reduction among the control animals. In the myocardial infarction group, five of 24 dogs (21%) were inducible before flow reduction. However, 50% flow reduction in the myocardial infarction group resulted in inducibility of ventricular tachycardia in 12 of 24 dogs (50%); nine of 16 (56%) during 75% flow reduction; and six of 11 (55%) with 100% flow reduction. In addition, none of the dogs in the myocardial infarction group developed spontaneous ventricular fibrillation during 25% or 50% flow reduction, whereas six of 22 (27%) developed ventricular fibrillation during 75% flow reduction and 10 of 21 (48%) during 100% flow reduction. In dogs with spontaneous ventricular fibrillation during flow reduction, the total myocardial mass of the ischemic "risk" zone and infarcted zone was significantly greater than in those without spontaneous ventricular fibrillation (68 +/- 5% versus 56 +/- 6% [p less than 0.01]). There was no difference in the total myocardial mass of the ischemic risk zone and infarcted zone between dogs with and without inducible ventricular tachycardia during flow reduction.

CONCLUSIONS

In canine model of subacute myocardial infarction, superimposed ischemia increased the likelihood of inducible sustained ventricular tachycardia with lesser grades of coronary flow reduction compared with that necessary to allow spontaneous ventricular fibrillation. The underlying pathophysiology appears to differ between spontaneous ventricular fibrillation and electrically induced sustained ventricular tachycardia.
Effects of short-term, diet-induced hypercholesterolemia on systemic hemodynamics, myocardial blood flow, and infarct size in awake dogs with acute myocardial infarction.
Authors: Sakamoto S , Kashiki M , Imai N , Liang C S , Hood W B
Published: June 2012

BACKGROUND

Short-term cholesterol feeding has been shown to affect vasomotor tone and increase infarct size in anesthetized rabbits. The purpose of the study was to determine whether acute hypercholesterolemia reduced collateral flow to ischemic myocardium and increased infarct size in the awake dog.

METHODS AND RESULTS

Acute myocardial infarction was produced in awake dogs by a 4-hour left anterior descending coronary artery occlusion followed by 6-hour reperfusion after either a cholesterol-supplemented diet (n = 14) or a control diet of dog chow (n = 15) for 10 days. Infarct size was determined using nitroblue tetrazolium staining. In two subgroups, a 15-minute transient occlusion of the left anterior descending coronary artery was produced before the diet treatments and was compared with occlusion after diet treatments, so that the effects of hypercholesterolemia of collateral flow could be determined by paired comparisons. Cholesterol feeding increased plasma cholesterol to 288 +/- 52 mg/dl, which was twofold to threefold that in the control group (127 +/- 35 mg/dl), but had no effects on baseline systemic hemodynamics and myocardial blood flow. Coronary artery occlusion produced similar increases in heart rate, mean aortic pressure, left atrial pressure, and plasma norepinephrine in both groups of animals. However, cholesterol feeding reduced collateral flow to ischemic myocardium and increased infarct size, compared with the control group. The infarct size correlated with ischemic myocardial blood flow in both groups, but the slopes of regression lines relating the two variables did not differ between the two groups.

CONCLUSIONS

Short-term, diet-induced hypercholesterolemia increased infarct size in awake dogs. This change results, at least in part, from a decrease in collateral blood flow to ischemic myocardium during coronary artery occlusion.
Prognostic significance of atrial fibrillation in advanced heart failure. A study of 390 patients.
Authors: Middlekauff H R , Stevenson W G , Stevenson L W
Published: June 2012

BACKGROUND

Atrial fibrillation is common in advanced heart failure, but its prognostic significance is controversial.

METHODS AND RESULTS

We evaluated the relation of atrial rhythm to overall survival and sudden death in 390 consecutive advanced heart failure patients. Etiology of heart failure was coronary artery disease in 177 patients (45%) and nonischemic cardiomyopathy or valvular heart disease in 213 patients (55%). Mean left ventricular ejection fraction was 0.19 +/- 0.07. Seventy-five patients (19%) had paroxysmal (26 patients) or chronic (49 patients) atrial fibrillation. Compared with patients with sinus rhythm, patients with atrial fibrillation did not differ in etiology of heart failure, mean pulmonary capillary wedge pressure on therapy, or embolic events but were more likely to be receiving warfarin and antiarrhythmic drugs and had a slightly higher left ventricular ejection fraction. After a mean follow-up of 236 +/- 303 days, 98 patients died: 56 (57%) died suddenly, and 36 (37%) died of progressive heart failure. Actuarial 1-year overall survival was 68%, and sudden death-free survival was 79%. Actuarial survival was significantly worse for atrial fibrillation than for sinus rhythm patients (52% versus 71%, p = 0.0013). Similarly, sudden death-free survival was significantly worse for atrial fibrillation than for sinus rhythm patients (69% versus 82%, p = 0.0013). By Cox proportional hazards model, pulmonary capillary wedge pressure on therapy, left ventricular ejection fraction, coronary artery disease, and atrial fibrillation were independent risk factors for total mortality and sudden death. For patients who had pulmonary capillary wedge pressure of less than 16 mm Hg on therapy, atrial fibrillation was associated with poorer 1-year survival (44% versus 83%, p = 0.00001); however, in the high pulmonary capillary wedge pressure group, atrial fibrillation did not confer an increased risk (58% versus 57%).

CONCLUSIONS

Atrial fibrillation is a marker for increased risk of death, especially in heart failure patients who have lower filling pressures on vasodilator and diuretic therapy. Whether aggressive attempts to maintain sinus rhythm will reduce this risk is unknown.
Streptokinase-induced platelet aggregation. Prevalence and mechanism.
Authors: Vaughan D E , Van Houtte E , Declerck P J , Collen D
Published: June 2012

BACKGROUND

Streptokinase (SK) is a bacteria-derived protein and one of the plasminogen activators that is currently available for therapeutic use. Exposure to SK induces synthesis of specific antibodies that may initiate platelet aggregation and paradoxical clot propagation during treatment.

METHODS AND RESULTS

Using platelet-rich plasma (PRP), we found that SK (5,000 units/ml) but not urokinase (2,500 units/ml) or recombinant tissue-type plasminogen activator (2,500 units/ml) caused platelet aggregation in PRP from 14 of 100 normal volunteers. In 13 consecutive patients treated with SK for acute myocardial infarction, SK-mediated platelet aggregation was induced in five patients within 1 week after treatment. SK-mediated platelet aggregation was associated with significantly increased titers of both anti-SK antibodies and SK-neutralizing activity in plasma; it was partially inhibited by aspirin (1 mM) and by aprotinin (500 kallikrein inhibitor units/ml) and completely inhibited by tranexamic acid (1 mM) and by prostaglandin E1 (9 microM). Addition of SK (1,000 or 5,000 units/ml) induce a statistically significant dose-dependent thromboxane B2 release in mixtures of PRP with plasma from subjects with SK-induced aggregation but not in samples of PRP mixed with plasma from nonresponders; addition of recombinant tissue-type plasminogen activator (1 or 50 micrograms/ml) did not induce thromboxane B2 release. Mixing experiments with PRP and immunoglobulin G from reactive and nonreactive donors revealed that SK-induced aggregation requires the presence of anti-SK antibodies. When 125I-SK (50 nM) was used, platelets preincubated with plasminogen (0.5 microM) bound 9,500 +/- 600 (mean +/- SEM, n = 6) molecules SK/platelet, which increased to 25,000 +/- 3,100 molecules/platelet after thrombin stimulation. Tranexamic acid (1 mM) blocked specific binding of SK to resting platelets.

CONCLUSIONS

These data demonstrate that SK-induced platelet aggregation is initiated by the binding of anti-SK antibodies to the SK-plasminogen complex located on the platelet surface. SK-induced platelet activation may limit the therapeutic effectiveness of the drug, and in view of the high prevalence of aggregation in a normal population, prospective evaluation of the effects of platelet aggregation during treatment with SK is warranted.
Post-myocardial infarction mortality in patients with ventricular premature depolarizations. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Pilot Study.
Authors: Cairns J A , Connolly S J , Gent M , Roberts R
Published: June 2012

BACKGROUND

Among survivors of acute myocardial infarction, frequent and repetitive ventricular premature depolarizations (VPDs) detected on ambulatory monitoring contribute independently to the risk of all-cause mortality and sudden death. Apart from the beta-blockers, no antiarrhythmic drug has been reliably demonstrated to reduce mortality among patients with VPDs. A pilot study was undertaken to gather data to aid in the design of a multicenter trial of amiodarone for the reduction of mortality from cardiac arrhythmias in such patients.

METHODS AND RESULTS

Seventy-seven patients with acute myocardial infarction within the previous 6-30 days and 10 or more VPDs/hr or one or more runs of ventricular tachycardia on 24-hour electrocardiographic recording were randomized in a double-blind fashion in a 2:1 amiodarone-to-placebo ratio. The loading dose was 10 mg/kg/day for 3 weeks. The maintenance dose was 300-400 mg/day with reductions at 4-month intervals in response to VPD suppression, excessive plasma levels, or toxicity. VPD suppression at 1 week and 2 weeks was 63% and 85%, respectively, on amiodarone and 17% and 27%, respectively, on placebo. Apart from thyroid-stimulating hormone elevation and skin reactions, no side effects occurred more frequently with amiodarone. The study drug was stopped for side effects or noncompliance in 35% of amiodarone patients and 34% of placebo patients. Patients were followed for a maximum of 2 years (mean, 20 months). Arrhythmic death or resuscitated ventricular fibrillation occurred in two of 48 amiodarone patients (6%) and four of 29 placebo patients (14%), whereas the rates of all-cause mortality were five of 48 (10%) and six of 29 (21%), respectively.

CONCLUSIONS

Amiodarone, in moderate loading and maintenance dosages with adjustments in response to plasma levels, VPD suppression, and side effects, results in effective VPD suppression and acceptable levels of toxicity.
Predictors of first discharge and subsequent survival in patients with automatic implantable cardioverter-defibrillators.
Authors: Levine J H , Mellits E D , Baumgardner R A , Veltri E P , Mower M , Grunwald L , Guarnieri T , Aarons D , Griffith L S
Published: June 2012

BACKGROUND

Two hundred eighteen patients were evaluated in a two-phase approach (time to first appropriate discharge, survival after discharge) to identify factors that may be related to maximal benefit derived from use of an automatic implantable cardioverter-defibrillator (AICD).

METHODS AND RESULTS

One hundred ninety-seven patients survived implantation of AICD, with or without concomitant cardiac surgery. One hundred five patients had an AICD discharge associated with syncope, presyncope, documented sustained ventricular tachycardia or fibrillation, or sleep at 9.1 +/- 11.1 months after implantation. Patients survived 23.8 +/- 18.0 months after AICD discharge. Left ventricular dysfunction (p = 0.008 for ejection fraction less than 25%) was associated with earlier AICD discharge and shortened survival after AICD discharge (p = 0.008 for ejection fraction less than 25%; p = 0.01 for New York Heart Association functional class III and IV). beta-Blocker administration (p = 0.006) and coronary bypass surgery (p = 0.06) were associated with later AICD discharge. Coronary bypass surgery (p = 0.035) but not beta-blockers was associated with more prolonged survival after AICD discharge.

CONCLUSIONS

These data suggest that a relatively easy algorithm can be applied to predict which patient will benefit most from AICD implantation.
Suppression of eicosanoid biosynthesis during coronary angioplasty by fish oil and aspirin.
Authors: Braden G A , Knapp H R , FitzGerald G A
Published: June 2012

BACKGROUND

Percutaneous transluminal coronary angioplasty (PTCA) is an acute, localized stimulus to platelet and vascular function. Periprocedural cardiovascular complications are reduced by moderate-dose aspirin (ASA), presumably due to inhibition of thromboxane (TX) A2.

METHODS AND RESULTS

Excretion of TXA2 and prostacyclin (PGI2) metabolites in urine increased during PTCA. Pretreatment for 3 days with either moderate- (325 mg/day) or low-dose (80 mg/day) ASA inhibited the increase in both eicosanoids. Pretreatment for 3 weeks with fish oil (10 g/day) only partially suppressed TXA2. Formation of trienoic eicosanoids and accumulation of omega-3 fatty acids in platelet membranes confirmed fish oil ingestion. Although basal PGI2 was not inhibited, the PTCA-related increment was suppressed.

CONCLUSIONS

PTCA results in an acute, transient alteration of eicosanoid biosynthesis consistent with accelerated platelet-vascular interactions. Pretreatment for 3 days with moderate or low doses of ASA suppresses TXA to a similar extent during PTCA, and their effects on acute cardiovascular complications of this procedure are likely to be comparable. It is unlikely that even prolonged pretreatment with fish oil can substitute for the platelet inhibitory action of ASA during PTCA. Suppression of PGI2 may contribute to the residual acute periprocedural complication rate in patients taking ASA.