bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise technetium-99m sestamibi tomography for cardiac risk stratification of patients with stable chest pain.
Authors: Stratmann H G , Williams G A , Wittry M D , Chaitman B R , Miller D D
Published: June 2012

BACKGROUND

This study was designed to evaluate the prognostic value of symptom-limited maximal exercise treadmill testing with tomographic technetium-99m sestamibi (MIBI) myocardial imaging in patients referred for evaluation of stable angina. Exercise stress thallium-201 myocardial imaging provides prognostic information in coronary artery disease subsets including patients with stable chest pain. The prognostic value of exercise technetium-99m MIBI myocardial tomography has not been established.

METHODS AND RESULTS

Of 548 consecutive patients with stable angina pectoris who underwent maximal exercise treadmill stress testing in combination with a same-day "rest-stress" tomographic technetium-99m MIBI myocardial imaging protocol, 521 patients were followed for 13 +/- 5 months to determine the univariate and multivariate variables associated with cardiac events and to define their cardiac event-free survival. Ten patients were lost to follow-up (98% complete), and 17 who had coronary revascularization within 6 months of testing were excluded. Major cardiac events occurred in 24 patients (9%)--nonfatal myocardial infarction in 11 and cardiac death in 13. Univariate Cox survival analysis demonstrated significant relative risk (RR) and 95% confidence intervals (CI) for exercise ST segment depression (RR = 2.3; 95% CI, 1.0 to 5.3), an abnormal MIBI scan (RR = 13.8; 95% CI, 1.9 to 102.3), and a reversible MIBI perfusion defect (RR = 3.2; 95% CI, 1.4 to 7.5). Multivariate models demonstrated that both exercise MIBI perfusion abnormalities (RR = 11.9; 95% CI, 1.6 to 89.4) and reversible MIBI perfusion defects (RR = 2.9; 95% CI, 1.2 to 7.0) had independent predictive value. During 1 year of follow-up, cardiac events occurred in only 0.5% of patients with normal MIBI scans compared with 7% of those with abnormal MIBI scans (P < .001). One-year, cardiac event-free survival was 92% in patients with reversible MIBI perfusion defects (P < .01 versus normal), 96% in patients with fixed defects (P < .01), and 93% in patients with combined reversible and fixed MIBI myocardial perfusion abnormalities (P < .02).

CONCLUSIONS

As with exercise thallium-201 myocardial imaging, exercise stress technetium-99m MIBI myocardial tomography provides significant independent information concerning the subsequent risk of serious cardiac events (death, myocardial infarction) in patients with stable angina pectoris. The identification of MIBI perfusion abnormalities, in particular, the presence of reversible MIBI defects, was associated with reduced 1-year, event-free survival. The recognized imaging and radiotracer biokinetic differences between thallium-201 and MIBI do not appear to modulate the prognostic value associated with scintigraphic evidence of ischemic myocardial jeopardy in the stable angina population.
Low-dose aspirin inhibits platelet-induced contraction of the human isolated coronary artery. A role for additional 5-hydroxytryptamine receptor antagonism against coronary vasospasm?
Authors: Bax W A , Renzenbrink G J , van der Linden E A , Zijlstra F J , van Heuven-Nolsen D , Fekkes D , Bos E , Saxena P R
Published: June 2012

BACKGROUND

The beneficial effect of low-dose aspirin in the prevention of coronary vasospasm is well documented. In this study, we investigated the contractile effect of human washed platelets on the human isolated coronary artery. We concentrated on the effect of low-dose aspirin (40 mg/d) taken by the platelet donor and on the efficacy of thromboxane A2 (TXA2) and 5-hydroxytryptamine (5-HT) receptor antagonists.

METHODS AND RESULTS

Human coronary artery segments were suspended in an organ bath set-up for isometric tension measurement. Platelets (10(9) to 3 x 10(10)/L) elicited concentration-dependent contractile responses of the coronary artery segments, reaching 28.4 +/- 7.1% of contractions induced by 100 mmol/L K+. The contractile response tended to be decreased in vessel segments with histological signs of early atherosclerosis. Contraction was significantly attenuated after pretreatment of the vessel segments with ketanserin (5-HT2 receptor antagonist, 1 mumol/L) or SQ30741 (TXA2 receptor antagonist, 0.01 mumol/L), reaching 8.8 +/- 2.3% and 3.2 +/- 2.2% of contraction to 100 mmol/L K+, respectively. Platelets obtained from the same platelet donors after they had taken aspirin (40 mg/d for 7 to 13 days) caused significantly lower contractile responses (7.6 +/- 2.7% of 100 mmol/L K+) associated with an almost selective inhibition of the synthesis of thromboxane measured in the organ bath solution (untreated platelets, 2.19 +/- 0.43 nmol/L; aspirin-treated platelets, 0.66 +/- 0.05 nmol/L). The amount of 5-HT secreted in the organ bath remained unaltered (65.17 +/- 9.94 and 64.03 +/- 8.98 nmol/L, respectively). This explains why ketanserin significantly attenuated the residual contractile responses caused by platelets obtained from aspirin-treated subjects, whereas SQ30741 caused minor, nonsignificant additional attenuation.

CONCLUSIONS

The results of the present study therefore suggest that additional antagonism of the contractile 5-HT receptors in the coronary artery may increase the efficacy of low-dose aspirin in vivo.
Effect of acute magnesium administration on the frequency of ventricular arrhythmia in patients with heart failure.
Authors: Sueta C A , Clarke S W , Dunlap S H , Jensen L , Blauwet M B , Koch G , Patterson J H , Adams K F
Published: June 2012

BACKGROUND

There is a high incidence of ventricular arrhythmia and sudden death in patients with heart failure. Unfortunately, currently available antiarrhythmic agents have only limited efficacy and may result in proarrhythmia and hemodynamic deterioration in these patients.

METHODS AND RESULTS

We studied the acute effect of intravenous magnesium chloride on the frequency and severity of ventricular arrhythmia in 30 patients with symptomatic heart failure using a double-blind, placebo-controlled crossover design. The left ventricular ejection fraction was 23.0 +/- 8.0% (mean +/- SD). No patient had a history of symptomatic ventricular arrhythmia or was receiving antiarrhythmic agents, calcium channel antagonists, or beta-blockers. Patients were randomized to receive placebo (5% dextrose [D5W] in water alone) or magnesium chloride in D5W given as a bolus of 0.3 mEq/kg over 10 minutes followed by a maintenance infusion of 0.08 mEq/kg per hour for 24 hours. The magnesium concentrations 30 minutes and 24 hours after the bolus were 3.6 +/- 0.1 and 4.2 +/- 0.1 mg/dL, respectively. There was no significant change in serum potassium concentration during magnesium administration. Blinded analysis revealed that administration of intravenous magnesium chloride, compared with placebo, significantly decreased total ventricular ectopy per hour (mean +/- SEM, 70 +/- 26 versus 149 +/- 64, P < .001), couplets per day (23 +/- 11 versus 94 +/- 59, P = .007), and episodes of ventricular tachycardia per day (0.8 +/- 0.2 versus 2.6 +/- 1.0, P = .051).

CONCLUSIONS

Intravenous magnesium chloride administration reduces the frequency of ventricular arrhythmia in patients with symptomatic heart failure.
Effect of transcutaneous electrical nerve stimulation on coronary blood flow.
Authors: Chauhan A , Mullins P A , Thuraisingham S I , Taylor G , Petch M C , Schofield P M
Published: June 2012

BACKGROUND

Although neurostimulation has been shown to be of benefit in angina pectoris, the exact mechanism of its action is not clear. This study was performed to examine the effect of transcutaneous electrical nerve stimulation on coronary blood flow.

METHODS AND RESULTS

The effect of transcutaneous electrical nerve stimulation was studied in 34 syndrome X patients (group 1), 15 coronary artery disease patients (group 2), and 16 heart transplant patients (group 3). Coronary blood flow velocity (CBFV) in the left coronary system was measured at rest and after a 5-minute stimulation period with a Judkins Doppler. There was a significant increase in the resting CBFV in group 1 (from 6.8 +/- 4.1 to 10.5 +/- 5.7 cm/s, P < .001) and group 2 (from 6.8 +/- 4.1 to 10.5 +/- 5.7 cm/s, P < .001). However, there was no significant change in the resting CBFV in group 3. There were no significant changes in the coronary arterial diameters as a result of neurostimulation. There was a significant decrease in the epinephrine levels in group 1 (from 79.6 +/- 17.8 to 58.5 +/- 17.5 ng/L, P = .01) and group 2 (from 102.2 +/- 27.2 to 64.1 +/- 19.1 ng/L, P = .01).

CONCLUSIONS

Transcutaneous electrical nerve stimulation can increase resting coronary blood flow velocity. The findings suggest that the site of action is at the microcirculatory level and that the effects may be mediated by neural mechanisms.
Arterial imaging with a new forward-viewing intravascular ultrasound catheter, II. Three-dimensional reconstruction and display of data.
Authors: Ng K H , Evans J L , Vonesh M J , Meyers S N , Mills T A , Kane B J , Aldrich W N , Jang Y T , Yock P G , Rold M D
Published: June 2012

BACKGROUND: Current intravascular ultrasound (IVUS) catheters provide transverse imaging at the level of the ultrasound transducer. This limits imaging to large-diameter segments without critical atherosclerotic narrowings. We have developed a prototype 20-MHz forward-viewing IVUS catheter that provides two-dimensional sector imaging distal to the catheter tip. A present limitation of this technique is that the catheter must be manually rotated to obtain multiple longitudinal views required to integrate the segment into a three-dimensional matrix. To overcome this, we have developed an algorithm that reconstructs these multiple two-dimensional forward-viewing IVUS images into a three-dimensional matrix for more complete depiction of the segment distal to the ultrasound catheter. This algorithm allows display and multidimensional slicing of the three-dimensional reconstruction. METHODS AND RESULTS. To test our algorithms, five arterial segments (three canine aortas, two human femoral arteries) were evaluated in vitro. In each segment, 36 forward-viewing longitudinal slices were collected, digitized, processed, and reoriented to produce a three-dimensional reconstruction (3DR) matrix. The matrix data were sliced into parallel transverse sections and compared with morphometric interpretation of histological sections (Histo). As a result, image data could be reconstructed for a distance of 2.0 cm ahead of the catheter. 3DR easily demonstrated wall and luminal morphology and provided transverse IVUS images comparable to the histological specimens. A good correlation was noted between Histo- and 3DR-determined luminal diameters (LD) and luminal areas: 3DR LD = 1.4 Histo LD-0.4, r = .86; 3DR LD = 0.7 +/- 0.20 cm (mean +/- SD); and Histo LD = 0.7 +/- 0.13 cm. CONCLUSIONS: These preliminary data demonstrate the feasibility of 3DR of forward-viewing IVUS data. This method allows rapid, detailed analysis of diseased arterial segments previously unavailable with standard IVUS and may permit better targeting of interventional techniques.
Effects of beta-adrenergic blockade on immunologic and cardiovascular changes induced by mental stress.
Authors: Benschop R J , Nieuwenhuis E E , Tromp E A , Godaert G L , Ballieux R E , van Doornen L J
Published: June 2012

BACKGROUND

Acute mental stress evokes responses in the cardiovascular and the immune systems. In particular, the subset of natural killer (NK) cells is found to be responsive to mental stress. The role of beta-adrenergic mechanisms in these processes in the subject of this investigation.

METHODS AND RESULTS

Healthy male volunteers (n = 31) were subjected to two consecutive mental tasks. Subjects were randomly assigned to a beta-blocker (propranolol 40 mg) or a placebo group. The capsules were ingested 1 hour before the tasks. The tasks evoked sympathetic responses, as indicated by an increase in heart rate and a decrease in the preejection period. These effects were abolished under beta-blockade, indicating that effective beta-blockade was achieved. In the immune system, significant increases were found for the number of NK cells and NK cell activity in the placebo group; these increases were absent in the propranolol group. In addition, an increase in all lymphocyte subsets was observed in subjects who had ingested propranolol. This increase, however, was also observed in subjects who had received propranolol but had not performed the tasks, indicating that these non-subset-specific increases in lymphocytes were a side effect of the beta-blocker.

CONCLUSIONS

Mental stress induces activation of the sympathetic nervous system, with concomitant increases in the number of NK cells in the circulation. These changes were inhibited by propranolol, indicating that stress-induced increases in the number and activity of NK cells in the circulation are controlled by a beta-adrenergic mechanism.
Vascular injury augments adrenergic neurotransmission.
Authors: Candipan R C , Hsiun P T , Pratt R , Cooke J P
Published: June 2012

BACKGROUND

We have observed persistent desensitization to exogenous norepinephrine after balloon injury. We postulated that this desensitization may be due to a local increase in the release of neuronal norepinephrine.

METHODS AND RESULTS

New Zealand White rabbits underwent left iliac artery angioplasty; 4 weeks later, both iliac arteries were harvested. Maximal response to exogenous norepinephrine was reduced in injured compared with noninjured vessels (12.3 +/- 1.0 g versus 10.3 +/- 1.5 g; n = 7, P = .056). By contrast, response to electrical stimulation (to induce neuronal norepinephrine release) was significantly greater in injured tissues (36 +/- 7% versus 14 +/- 3%; values expressed as percent of maximal contraction to exogenous norepinephrine; P = .025). Direct measurement of tissue norepinephrine revealed a threefold increase 4 weeks after injury (1236 +/- 410 versus 466 +/- 97 pg/mg; injured versus noninjured). To determine if desensitization to exogenous norepinephrine was due to a persistent increase in neuronal norepinephrine release, the experiments were repeated after chemical sympatholysis using 6-hydroxydopamine (6-OHDA) (65 mg/kg). To determine if activation of vascular angiotensin II contributed to facilitation of adrenergic neurotransmission, other animals received ramipril (RAM; 1 mg/kg per day). Both treatments were initiated 7 days before angioplasty. In the 6-OHDA group there was no evidence of desensitization, judged by maximal response to exogenous norepinephrine (7.5 +/- 0.6 versus 7.5 +/- 0.8, noninjured versus injured). Similar results were obtained in RAM animals (9.9 +/- 0.8 versus 9.6 +/- 1.2, noninjured versus injured).

CONCLUSIONS

This is the first study to demonstrate enhanced adrenergic neurotransmission after balloon injury. The facilitation of adrenergic neurotransmission may be due to increased local concentrations of angiotensin II and is associated with desensitization to exogenous norepinephrine.
Induction of myocardial insulin-like growth factor-I gene expression in left ventricular hypertrophy.
Authors: Donohue T J , Dworkin L D , Lango M N , Fliegner K , Lango R P , Benstein J A , Slater W R , Catanese V M
Published: June 2012

BACKGROUND

Left ventricular hypertrophy is a generalized adaptation to increased afterload, but the growth factors mediating this response have not been identified. To explore whether the hypertrophic response was associated with changes in local insulin-like growth factor-I (IGF-I) gene regulation, we examined the induction of the cardiac IGF-I gene in three models of systolic hypertension and resultant hypertrophy.

METHODS AND RESULTS

The model systems were suprarenal aortic constriction, uninephrectomized spontaneously hypertensive rats (SHR), and uninephrectomized, deoxycorticosterone-treated, saline-fed rats (DOCA salt). Systolic blood pressure reached hypertensive levels at 3 to 4 weeks in all three systems. A differential increase in ventricular weight to body weight (hypertrophy) occurred at 3 weeks in the SHR and aortic constriction models and at 4 weeks in the DOCA salt model. Ventricular IGF-I mRNA was detected by solution hybridization/RNase protection assay. IGF-I mRNA levels increased in all three systems coincident with the onset of hypertension and the development of ventricular hypertrophy. Maximum induction was 10-fold over control at 5 weeks in the aortic constriction model, 8-fold at 3 weeks in the SHR, and 6-fold at 6 weeks in the DOCA salt model. IGF-I mRNA levels returned to control values by the end of the experimental period despite continued hypertension and hypertrophy in all three systems. In contrast, ventricular c-myc mRNA content increased twofold to threefold at 1 week and returned to control levels by 2 weeks. Ventricular IGF-I receptor mRNA levels were unchanged over the time course studied. The increased ventricular IGF-I mRNA content was reflected in an increased ventricular IGF-I protein content, as determined both by radioimmunoassay and immunofluorescence histochemistry.

CONCLUSIONS

We conclude that (1) hypertension induces significant increases in cardiac IGF-I mRNA and protein that occur coordinately with its onset and early in the development of hypertrophy, (2) IGF-I mRNA levels normalize as the hypertrophic response is established, (3) in comparison to IGF-I, both c-myc and IGF-I receptor genes are differentially controlled in experimental hypertension. These findings suggest that IGF-I may participate in initiating ventricular hypertrophy in response to altered loading conditions. The consistency of these findings in models of high-, moderate-, and low-renin hypertension suggests that they occur independently of the systemic renin-angiotensin endocrine axis.
Digital angiographic impulse response analysis of regional myocardial perfusion. Detection of autoregulatory changes in nonstenotic coronary arteries induced by collateral flow to adjacent stenotic arteries.
Authors: Schühlen H , Eigler N L , Whiting J S
Published: June 2012

BACKGROUND

Our study compares the effect of acute proximal stenosis of a coronary artery supplying a myocardial perfusion bed with that of stenosis of an adjacent artery resulting in collateral flow diversion supplied by the same perfusion bed. These alterations in coronary physiology were quantified by digital angiographic impulse response analysis of contrast material mean transit time for the coronary microcirculation, Tmicro, and by flowmeter and microsphere assessment of flow and regional flow distribution.

METHODS AND RESULTS

In 25 open-chest, anesthetized dogs, progressive circumflex artery stenosis led to a concordant decrease of circumflex artery resting and hyperemic flow, coronary flow reserve, and inverse angiographic mean transit time Tmicro-1 (P < .01). Progressive left anterior descending artery stenosis led to no or only minor changes of circumflex artery resting or hyperemic flow or flow reserve; only occlusion induced a significant decrease of coronary flow reserve (from 4.0 +/- 0.7 to 3.2 +/- 0.5, P < .05), whereas resting flow was increased by +8.6 +/- 5.9%. In contrast, circumflex artery Tmicro-1 diminished significantly with critical left anterior descending artery stenosis and occlusion (from 16.7 +/- 4.2 to 12.6 +/- 2.2 [P < .05] and 12.0 +/- 3.0 min-1 [P < .01], respectively). In 8 dogs, collateral flow induced by left anterior descending artery occlusion was quantified by microsphere injections. The decrease of circumflex artery Tmicro-1 correlated with the magnitude of collateral flow (r = .76) and was associated with the angiographic extent of collateral filling.

CONCLUSIONS

Digital angiographic impulse response analysis is a sensitive method to detect the influence of proximal artery stenosis on an artery's myocardial perfusion bed as well as the changes induced by an adjacent artery stenosis inducing collateral flow diversion from the supplying myocardial perfusion zone.
Effect of physical training on exercise-induced hyperkalemia in chronic heart failure. Relation with ventilation and catecholamines.
Authors: Barlow C W , Qayyum M S , Davey P P , Conway J , Paterson D J , Robbins P A
Published: June 2012

BACKGROUND

The exercise-induced rise in arterial potassium concentration ([K+]a) may contribute to exercise hyperpnea and could play a role in exertional fatigue. This study was designed to determine whether the exercise-induced rise in [K+]a is altered in patients with chronic heart failure (CHF) and whether physical training affects K+ homeostasis.

METHODS AND RESULTS

We evaluated 10 subjects with CHF (ejection fraction, 23 +/- 3.9%) and 10 subjects with normal left ventricular function (NLVF) who had undergone previous coronary artery graft surgery (ejection fraction, 63 +/- 8.6%). Subjects performed an incremental cycle ergometer exercise test before and after a physical training or detraining program. Changes in [K+]a and ventilation (VE) during exercise were closely related in both groups. Subjects with CHF did less absolute work and had reduced maximal oxygen consumption (VO2max) compared with subjects with NLVF (P < .01). Exercise-induced rises in [K+]a, VE, norepinephrine, lactate, and heart rate were greater at matched absolute work rates in subjects with CHF than in subjects with NLVF (P < .01). However, when the rise in [K+]a was plotted against percentage of VO2max to match for relative submaximal effort, there were no differences between the two groups. Physical training resulted in reduced exercise-induced hyperkalemia at matched submaximal work rates in both groups (P < .01) despite no associated change in the concentration of arterial catecholamines. At maximal exercise when trained, peak increases in [K+]a were unaltered, but peak concentrations of catecholamines were raised (P < .05). The decrease in VE at submaximal work rates after training was not significant with this incremental exercise protocol, but both groups had an increased peak VE when trained (P < .01).

CONCLUSIONS

Exercise-induced rises in [K+]a, catecholamines, and VE are greater at submaximal work rates in subjects with CHF than in subjects with NLVF. Physical training reduces the exercise-induced rise in [K+]a but does not significantly decrease VE during submaximal exercise with this incremental cycle ergometry protocol. The reduction in exercise-induced hyperkalemia after training is not the result of altered concentrations of arterial catecholamines. The pathophysiological significance of the increased exercise-induced hyperkalemia in CHF and the mechanisms of improved K+ homeostasis with training have yet to be established.
Inhibition of atherosclerosis by dietary pectin in microswine with sustained hypercholesterolemia.
Authors: Cerda J J , Normann S J , Sullivan M P , Burgin C W , Robbins F L , Vathada S , Leelachaikul P
Published: June 2012

Sustained hypercholesterolemia is a known risk factor for development of atherosclerosis. In animal studies, grapefruit pectin fed concurrently with a high-lipid diet inhibits hypercholesterolemia and atherogenesis. The purpose of the present study was to determine if grapefruit pectin affects cholesterol levels and atherogenesis of animals with established hypercholesterolemia. Microswine were fed an atherogenic diet to establish hypercholesterolemia. Plasma cholesterol levels rose rapidly and for 360 days were sustained at levels 6- to 12-fold the normal level. Then, half the microswine, selected at random, were fed a diet in which 3% grapefruit pectin was substituted for cellulose, and the remaining animals received the original diet. Animals were killed 270 days later, and the extent of atherosclerosis was determined. In animals with established hypercholesterolemia, pectin did not lower their cholesterol levels. However, pectin reduced the extent of atherosclerosis in both the aorta and coronary arteries. The mean surface area covered by atherosclerosis in the aorta was 13.6% in the group that did not receive pectin compared with 5.3% in the group that did receive pectin. The mean coronary artery narrowing was 45% without pectin and 24% with pectin. We conclude that pectin may have a direct beneficial effect on atherosclerosis by a mechanism independent of cholesterol levels.
Vesnarinone, a new inotropic agent, inhibits cytokine production by stimulated human blood from patients with heart failure.
Authors: Matsumori A , Shioi T , Yamada T , Matsui S , Sasayama S
Published: June 2012

BACKGROUND

Vesnarinone, a quinolinone derivative, is a recently synthesized positive inotropic agent that has been shown to dramatically improve the survival of patients with heart failure. However, the mechanism of action of vesnarinone remains unknown. Reversible neutropenia complicated with vesnarinone therapy suggests that vesnarinone may modulate the production of cytokines. Because tumor necrosis factor (TNF)-alpha and other cytokines have been shown to depress myocardial contractility, we investigated the effects of vesnarinone on the production of various cytokines.

METHODS AND RESULTS

We studied the effects of vesnarinone on cytokine production by lipopolysaccharide (LPS)-stimulated whole blood from seven patients with heart failure and from five healthy volunteers. Heparinized blood was diluted in RPMI and stimulated with LPS. Vesnarinone was added in a range of 1 to 30 micrograms/mL, the blood was incubated for 24 hours, and interleukin (IL)-1 alpha, IL-1 beta, IL-6, TNF-alpha, interferon (IFN)-gamma, and granulocyte colony-stimulating factor (G-CSF) were measured by an enzyme-linked immunosorbent assay. LPS stimulation induced a more prominent increase in TNF-alpha in patients with heart failure than in healthy volunteers. Vesnarinone inhibited the production of TNF-alpha and IFN-gamma both in healthy volunteers and in patients with heart failure. IL-1 alpha and IL-1 beta were also suppressed in healthy volunteers, but this response was variable, and a significant reduction was not seen in patients with heart failure. Marked inhibition of G-CSF and other cytokines by vesnarinone was observed in one patient who had developed neutropenia as a result of vesnarinone therapy.

CONCLUSIONS

Although the number of study patients was small and the results are preliminary, these findings provide evidence that vesnarinone plays an important role in the regulation of cytokines and suggest that the reduction of cytokine release may contribute to the beneficial effects of the drug in the treatment of heart failure. Furthermore, the measurement of cytokines may be useful in predicting the occurrence of neutropenia, which has been occasionally reported in patients treated with vesnarinone.
A new approach for local intravascular drug delivery. Iontophoretic balloon.
Authors: Fernández-Ortiz A , Meyer B J , Mailhac A , Falk E , Badimon L , Fallon J T , Fuster V , Chesebro J H , Badimon J J
Published: June 2012

BACKGROUND

Catheter-based systems are being developed to deliver drugs directly into the vessel wall. Pressure-mediated trauma and lack of homogeneous delivery are key limitations of these approaches.

METHODS AND RESULTS

We studied a new catheter-based delivery system that uses electrical current to force the drug into the vessel wall. The in vivo feasibility of this approach has been assessed by delivering 125I-hirudin into porcine carotid arteries. Vascular levels of hirudin after active iontophoresis (4 mA/cm2, 5 minutes) were 80-fold greater than those achieved by passive diffusion (without electricity). Tissue hirudin levels declined over time; by 1 hour after delivery, 80% of the drug had left the vessel wall, and by 3 hours later, the levels of hirudin within the wall were similar to those achieved by passive diffusion. Autoradiography revealed distribution of the drug throughout the entire circumference of the arterial wall within the intima, media, and adventitia. Iontophoresis-mediated vessel wall trauma was minimal (less than 10% endothelial denudation and medial smooth muscle cell damage). Balloon injury after local delivery changed neither kinetics nor distribution of the drug into the arterial wall.

CONCLUSIONS

(1) High local concentrations of hirudin in the arterial wall may be achieved with the iontophoretic balloon catheter. (2) The drug is distributed throughout the entire vessel wall without significant damage. (3) The retention of hirudin in the arterial wall is time dependent. (4) This technique might be useful to deliver therapeutic agents before or after percutaneous vascular interventions.
Use of therapeutic ultrasound in percutaneous coronary angioplasty. Experimental in vitro studies and initial clinical experience.
Authors: Siegel R J , Gunn J , Ahsan A , Fishbein M C , Bowes R J , Oakley D , Wales C , Steffen W , Campbell S , Nita H
Published: June 2012

BACKGROUND

Previous studies have shown the feasibility of peripheral arterial ultrasound angioplasty.

METHODS AND RESULTS

In this report, we describe the use of percutaneous therapeutic ultrasound for coronary angioplasty. In vitro, 11 postmortem, atherosclerotically occluded coronary arteries were obtained to assess catheter-delivered ultrasound for arterial recanalization as well as for assessment of the size of particulate debris. Clinically, coronary ultrasound angioplasty was performed in 19 patients (mean age, 56 years) to assess safety and feasibility for the treatment of obstructive coronary atherosclerosis. Three patients with unstable angina and 16 with exercise-induced myocardial ischemia were treated with a prototype 4.6F coronary catheter ultrasound ablation device with a 1.7-mm diameter ball tip. The ultrasound coronary catheter delivered ultrasound energy at 19.5 kHz, with a power output of 16 to 20 W at the transducer. Energy is delivered in a pulsed mode with a 50% duty cycle of 30 milliseconds. Patients were treated for a mean of 493 seconds (range, 130 to 890) with intracoronary ultrasound ablation. All lesions were treated with adjunctive balloon angioplasty. All 11 postmortem coronary occlusions were recanalized, and 99% of the particulates generated were < 10 microns in diameter. We found that after ultrasound, mean (+/- SD) coronary arterial stenosis fell from 80 +/- 12% to 60 +/- 18% (P < .001) and to 26 +/- 11% (P < .001) after adjunctive balloon angioplasty. Mean pressures required to achieve full balloon inflation were 2.7 atm (range, 1 to 5.5) with a median of 3.0-mm balloon size (2.5 to 3.5). No ultrasound-related complications were identified.

CONCLUSIONS

Intracoronary ultrasound plaque ablation appears to be safe. Our findings suggest that catheter-delivered high-intensity, low-frequency ultrasound may be useful for lesion debulking and enhancing arterial distensibility, allowing balloon dilation at relatively low pressures.
Involvement of 5-HT2 receptors in chronic endothelial dysfunction after balloon injury of porcine coronary arteries.
Authors: Shibano T , Vanhoutte P M
Published: June 2012

BACKGROUND

Endothelium-dependent, pertussis toxin-sensitive relaxation to 5-hydroxytryptamine (5-HT) is impaired selectively after balloon injury of porcine coronary artery, followed by regeneration of the endothelial cells. The present study was designed to test the hypothesis that 5-HT, released from aggregating platelets, affects the progression of the endothelial dysfunction.

METHODS AND RESULTS

Yorkshire pigs were assigned randomly to three groups: control group (standard diet), denudation group (high-cholesterol diet plus balloon denudation of the endothelium of coronary artery under fluoroscopy), and DV-7028-treated group (denudation group plus chronic treatment with the selective 5-HT2 receptor antagonist DV-7028, given from the first day on after balloon denudation). Four weeks after the denudation, quantitative angiography revealed that 5-HT injected into the coronary artery decreased the luminal diameter of the left anterior descending coronary artery at the denuded site in the denudation group but not in the control or the DV-7028-treated group. Then, animals were killed so we could study the endothelium-dependent responses of their coronary arteries in conventional organ chambers. The arteries from the denudation group exhibited less relaxation to 5-HT and sodium fluoride (a stimulant of G proteins) than those of the control group. Relaxations to 5-HT and sodium fluoride were greater in arteries from the DV-7028-treated group than in those from the denudation group. In contrast, the endothelium-dependent, pertussis toxin-insensitive relaxations to bradykinin and thrombin and the endothelium-independent relaxations to sodium nitroprusside and isoproterenol were not affected significantly by chronic treatment with DV-7028.

CONCLUSIONS

These results suggest that 5-HT2 receptors are involved in the chronic progression of endothelial dysfunction after balloon denudation in the porcine coronary artery.
Endothelin production in pulmonary circulation of patients with mitral stenosis.
Authors: Yamamoto K , Ikeda U , Mito H , Fujikawa H , Sekiguchi H , Shimada K
Published: June 2012

BACKGROUND

Although plasma endothelin concentrations are elevated in patients with pulmonary hypertension, the precise sites of endothelin production have not been defined. We investigated the endothelin production in the pulmonary circulation of patients with mitral stenosis and its effects on pulmonary vascular tone.

METHODS AND RESULTS

We measured plasma concentrations of endothelin-1, angiotensin II, and thrombomodulin in blood samples obtained from the right and left atria of 10 consecutive patients with rheumatic mitral stenosis (mean age, 55 years; range, 39 to 68) who were undergoing percutaneous mitral valvuloplasty. Plasma levels of endothelin-1 were significantly higher in the left atrium than in the right atrium (3.25 +/- 0.45 versus 2.53 +/- 0.36 pg/mL, mean +/- SE, P < .001). The increased plasma endothelin-1 level in the left atrium, which reflected endothelin-1 production in the pulmonary circulation, was correlated with mean pulmonary artery pressure (r = .65, P = .04), mean pulmonary arterial wedge pressure (r = .67, P = .03), total pulmonary resistance (r = .68, P = .03), and 1/mitral valve area (r = .85, P = .002) but not with pulmonary vascular resistance (r = .04, P = .91). There were no significant differences in plasma levels of angiotensin II and thrombomodulin between the right and left atria (angiotensin II, 16.40 +/- 3.08 versus 15.50 +/- 4.85 pg/mL; thrombomodulin, 2.96 +/- 0.34 versus 2.85 +/- 0.37 ng/mL).

CONCLUSIONS

Endothelin-1 production is increased in the pulmonary circulation of patients with mitral stenosis in response to increased pulmonary artery pressure but is not directly related to increased pulmonary vascular tone in this disorder.
Severe congenital mitral stenosis in infants.
Authors: Moore P , Adatia I , Spevak P J , Keane J F , Perry S B , Castaneda A R , Lock J E
Published: June 2012

BACKGROUND

Despite current medical and surgical therapy, infants with symptomatic congenital mitral stenosis (CMS) continue to have high rates of morbidity and mortality. Catheter balloon dilation has been successful in relieving symptoms in a few older children with CMS but has not been evaluated in infants.

METHODS AND RESULTS

We reviewed the records of 85 infants with CMS to assess severity of CMS, associated cardiac lesions, echocardiographic morphological appearance of the mitral valve, treatment, and outcome. There were five valve morphologies identified: "typical" hypoplastic mitral valve with symmetric papillary muscles (SYMM, 52%), supravalvar mitral ring (SVMR, 20%), double-orifice mitral valve (DOMV, 11%), hypoplastic mitral valve with asymmetric papillary muscles (ASYMM, 8%), and parachute mitral valve (PARA, 8%). Of the 85 infants, 31 (36%) were severely symptomatic, requiring intervention within the first 2 years. Balloon dilation was performed in 18 infants (age, 8.7 +/- 5.7 months; weight, 5.9 +/- 1.9 kg) and valve surgery in 13 (age, 10.9 +/- 5.9 months; weight, 6.7 +/- 2.1 kg). Balloon dilation decreased the peak transmitral gradient (LAa-LVED) > 30% in 15 of 18 initial attempts, from 20.3 +/- 8.2 to 10.9 +/- 4.9 mm Hg (P < .001), and the mitral valve area increased from 0.7 +/- 0.3 to 1.0 +/- 0.5 cm2/M2 (n = 10, P = .01). No infants died during the initial balloon dilation, although 2 of 3 died during a repeat procedure for restenosis. Other complications included significant mitral regurgitation in 7 of 18 patients (39%), 4 of whom had SVMR. Of the 18 infants, 8 (44%) had persistent symptomatic improvement at a mean follow-up of 14 months (range, 2 to 32 months). The 2-year survival after balloon dilation was 70%; 40% remained free of repeat intervention. Mitral valve surgery in 13 infants consisted of SVMR resections in 7, mitral valve replacements in 4, and LA-to-LV aortic valved homografts in 2. The operative mortality was 30%. Sustained improvement occurred in 8 (6 with SVMR) at 11 to 62 months of follow-up (mean, 30 months), with a 2-year survival of 60%.

CONCLUSIONS

Infants with severe CMS have 2-year mortality rates approaching 40% regardless of treatment modality. Balloon dilation significantly reduces the transmitral gradient in the majority, but symptomatic improvement persists in only 40%. Procedure-related mortality was associated with repeat balloon dilation in patients with left ventricular hypoplasia. Balloon dilation of "typical" CMS can provide symptomatic relief in many infants, allowing postponement of valve replacement, although infants with SVMR do better with surgical management.
Ventricular beats induce variations in cycle length of rapid (type II) atrial flutter in humans. Evidence of leading circle reentry.
Authors: Ravelli F , Disertori M , Cozzi F , Antolini R , Allessie M A
Published: June 2012

BACKGROUND

Slight variation in cycle lengths of common and rapid atrial flutter in humans is an established phenomenon, but its mechanisms have not been completely clarified. In a previous study, we demonstrated that in common atrial flutter the variations in atrial cycle length were due to atrial stretch affecting the revolution time of a reentrant circuit. In the present study, we investigate the nature of atrial cycle length variations in the rapid type of human atrial flutter.

METHODS AND RESULTS

Atrial interval variations of 17 episodes of rapid atrial flutter in 14 patients were investigated by measuring the sequence of atrial intervals from intraesophageal or intra-atrial leads and the onset of QRS complexes from a surface lead (V1). To study whether interval variation in flutter cycle was related to ventricular activity, a phase plot was constructed in which the flutter cycle length was plotted against the time after the previous QRS complex. This showed that the interval fluctuations were strictly coupled to the moment of ventricular activation. After the onset of the QRS complex, the rapid atrial flutter interval gradually decreased by an average of 4.1% (P < .001) and reached a minimum value after 300 to 600 milliseconds. Thereafter, the intervals increased again until the next ventricular beat occurred. In 10 patients developing both common and rapid atrial flutter, two different phase relations were found. Whereas during common atrial flutter the atrial interval increased after the QRS complex, it decreased during rapid atrial flutter. In three patients, intra-atrial pressure was recorded together with the electrical activity during both common and rapid atrial flutter episodes. This showed that variations in atrial flutter cycle length were associated with the rise of atrial pressure during ventricular contraction.

CONCLUSIONS

These findings indicate a role of contraction-excitation feedback caused by atrial stretch after a ventricular activation. The shortening of the atrial interval after the onset of the QRS complex as found in patients during rapid atrial flutter can be explained by stretch-induced shortening of atrial refractoriness and consequent shortening of the revolution time of a functionally determined intra-atrial circuit.
Effect of calcium channel block on the wall motion abnormality of the idiopathic long QT syndrome.
Authors: De Ferrari G M , Nador F , Beria G , Sala S , Lotto A , Schwartz P J
Published: June 2012

BACKGROUND

We recently showed the frequent occurrence of an unusual ventricular wall motion abnormality, assessed by echocardiography, in patients with the idiopathic long QT syndrome (LQTS). Two new quantitative indexes were developed: Th1/2 (time needed to reach half of the maximal systolic thickening), which was smaller in LQTS patients than in controls; and TSTh (time spent at a very low thickening rate before rapid relaxation), which was much greater in LQTS patients, indicating the presence of a slow contraction in the late thickening phase. This marked late systolic "plateau," either rectilinear or with a peculiar double peak pattern, was significantly more frequent in patients with a history of syncope or cardiac arrest. The mechanism underlying this puzzling phenomenon remained unexplained.

METHODS AND RESULTS

The present study assessed the effects of the calcium channel blocker verapamil on the contraction pattern in 10 LQTS patients (9 females and 1 male; mean age, 19 +/- 7 years) with a marked plateau pattern and in 6 healthy controls (4 females and 2 males; mean age, 28 +/- 5 years). Either verapamil (0.1 mg/kg) or saline was randomly injected over 2 minutes. Saline had no effect. In LQTS patients, verapamil increased Th1/2 by 27%, from 16.9 +/- 3.2% to 21.4 +/- 3.9% of the cardiac cycle (P = .005), and dramatically reduced TSTh by 92%, from 13.7 +/- 5.3% to 1.08 +/- 0.6% of the cardiac cycle (P < .00001). At the peak effect of verapamil, the contraction pattern of all patients was normal. In healthy control subjects, verapamil did not significantly change either Th1/2 (from 17.6 +/- 2.5% to 18.5 +/- 3.5% of the cardiac cycle) or TSTh (from 0.92 +/- 0.47% to 1.17 +/- 0.74%).

CONCLUSIONS

This study demonstrates that the wall motion abnormality of LQTS is completely abolished by verapamil. These results suggest that symptomatic LQTS patients may have an abnormal increase in the intracellular calcium concentration before relaxation has completed, possibly linked to an early afterdepolarization, and that the contraction abnormality may be the mechanical equivalent of an early afterdepolarization.
Vasodepressor reaction induced by inferior vena cava occlusion and isoproterenol in the rat. Role of beta 1- and beta 2-adrenergic receptors.
Authors: Waxman M B , Asta J A , Cameron D A
Published: June 2012

BACKGROUND

Testing for the susceptibility of vasodepressor reaction in humans involves the combination of restriction of venous return by passive upright tilting and the administration of isoproterenol. We developed an experimental rat model in which vasodepressor reactions are induced when the inferior vena cava is occluded during an infusion of isoproterenol. The reactions are characterized by the development of paradoxical bradycardia during the period of inferior vena cava occlusion.

METHODS AND RESULTS

Inferior vena cava occlusion was performed for 60 seconds, and the maximal changes in RR interval were measured during seven states as follows: (1) when inferior vena cava occlusion was performed under control conditions in 40 rats, the rate accelerated in all 40 rats (delta RR, -15.6 +/- 1.9 milliseconds in 25 rats, P < .001; delta RR, -13.3 +/- 1.7 milliseconds in 10 rats, P < .001); (2) when inferior vena cava occlusion was performed in 25 rats during an infusion of isoproterenol, a vasodepressor reaction was observed in all rats as the heart rate slowed (delta RR, +92.7 +/- 8.3 milliseconds, P < .001); (3) when inferior vena cava occlusion was performed in 10 rats during an infusion of dobutamine, a selective beta 1-agonist, a vasodepressor reaction was observed in all rats as the heart rate slowed (delta RR, +63.3 +/- 10.6 milliseconds, P < .001); (4) when inferior vena cava occlusion was performed in 5 rats during an infusion of salbutamol, a selective beta 2-agonist, vasodepressor reaction was not observed as the heart rate accelerated in all rats (delta RR, -11.4 +/- 2.8 milliseconds, P < .002); (5) the vasodepressor reaction induced by either dobutamine or isoproterenol was inhibited by atenolol, a selective beta 1-adrenergic receptor antagonist; (6) the vasodepressor reaction induced by isoproterenol was inhibited by propranolol (lipophilic) and sotalol (nonlipophilic) beta-blockers and there was a dose-dependent attenuation by propranolol of the maximal RR interval slowing during inferior vena cava occlusion; and (7) butoxamine, a selective beta 2-adrenergic receptor antagonist, attenuated but did not block the vasodepressor reaction observed during an infusion of isoproterenol.

CONCLUSIONS

Reduced cardiac volume combined with beta 1-adrenergic stimulation can stimulate a vasodepressor reaction in rats. beta 2-Adrenergic receptors play little or no role in the reaction. The vasodepressor reaction can be blocked by selective or nonselective beta 1-adrenergic antagonists independent of the drug's ability to penetrate the central nervous system. The application of these findings to humans remains to be elucidated.
Contraction uncoupling with butanedione monoxime versus low calcium or high potassium solutions on flow and contractile function of isolated hearts after prolonged hypothermic perfusion.
Authors: Stowe D F , Boban M , Graf B M , Kampine J P , Bosnjak Z J
Published: June 2012

BACKGROUND

Normal ionic perfusate containing butanedione monoxime (BDM), a reversible myofilament inhibitor, could be better than either a high potassium (KCl) or a low calcium (CaCl2) perfusate for long-term cardiac preservation. This hypothesis was tested in 70 isolated guinea pig hearts.

METHODS AND RESULTS

Three groups--time control (8 hours, 37 degrees C), cold control (22 hours, 3.8 degrees C), and cold+BDM (22 hours)--were perfused with typical Krebs-Ringer solution (2.5 mmol/L CaCl2 and 4.5 mmol/L KCl). Two other groups were cold perfused for 22 hours either with 2.5 mmol/L CaCl2 + 20 mmol/L KCl (high) or with 0.5 mmol/L CaCl2 (low) + 4.5 mmol/L KCl. These changes were maintained from 20 minutes before cold perfusion until 30 minutes after rewarming to 37 degrees C. Coronary vasodilator reserve was tested before cold perfusion and 2 hours after warm reperfusion with adenosine (Ade), acetylcholine (Ach, endothelium dependent), and nitroprusside (NP, endothelium independent). Each treatment decreased left ventricular pressure (LVP) by more than 80% before cold perfusion. During warm reperfusion, LVP was lower in cold control (-72 +/- 5%), high KCl (-76 +/- 4%), and low CaCl2 (-80 +/- 4%) groups than in BDM (-38 +/- 3%) or time control (-18 +/- 4%) groups; coronary flow (CF) was lower in high KCl (-67 +/- 4%) and low CaCl2 (-54 +/- 7%) groups than in cold control (-37 +/- 6%), BDM (-30 +/- 5%), or time control (+2 +/- 3%) groups; and percent oxygen extraction (controls, 62 +/- 4%) was higher in the high KCl group (83 +/- 6%) than in cold control (72 +/- 3%), BDM (73 +/- 3%), low CaCl2 (72 +/- 5%), or time control (63 +/- 3%) groups. CF responses to Ade, Ach, and NP (+103 +/- 7%, +24 +/- 5%, and +34 +/- 5% before cold) were attenuated (+76 +/- 6%, +18 +/- 5%, and +23 +/- 4%) in the time control group (5 hours later), were reduced but present in the BDM group (+10 +/- 5%, -5 +/- 5%, and -5 +/- 5%), and were absent in both low CaCl2 and high KCl groups after 2 hours of reperfusion.

CONCLUSIONS

Normal ionic BDM solution better preserves cardiac function and basal CF after prolonged cold perfusion than do cold control, high KCl, and low CaCl2 solutions. Vasodilatory capacity is markedly diminished after perfusion with either the high KCl or the low CaCl2 solution.