bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphological determinants of echocardiographic patterns of mitral valve systolic anterior motion in obstructive hypertrophic cardiomyopathy.
Authors: Klues H G , Roberts W C , Maron B J
Published: June 2012

BACKGROUND

The morphological determinants of mitral valve systolic anterior motion (SAM) and obstruction to left ventricular outflow in patients within the broad clinical spectrum of hypertrophic cardiomyopathy (HCM) are not completely understood, particularly the contribution of mitral leaflet length and size.

METHODS AND RESULTS

To clarify this issue, mitral valve specimens from 43 patients with HCM and basal outflow obstruction were used to relate morphometric measurements of leaflet area to certain morphological and functional assessments of left ventricular outflow tract geometry and valvular motion obtained from echocardiograms in the same patients. Twenty-four patients (56%) had mitral valves of normal size (leaflet area < 12.0 cm2) and 19 patients (44%) had enlarged and elongated valves (area > or = 12.0 cm2). Compared with normal-sized mitral valves, the enlarged valves were situated more posteriorly in a larger left ventricular outflow tract (cross-sectional area, 3.3 +/- 1.0 versus 1.9 +/- 0.7 cm2 for normal-sized valves; p < 0.001) and also had greater systolic excursion of the anterior leaflet (16.2 +/- 4.5 versus 13.3 +/- 3.3 mm, p < 0.02), usually with a distinctive sharp-angled bend and localized contact of the leaflet tip with ventricular septum ("typical" SAM); this pattern of SAM was possible because the central and distal portions of the leaflet were relatively free of fibrous thickening. In contrast, normal-sized mitral valves were situated more anteriorally in a smaller left ventricular outflow tract and frequently showed a different mechanism of SAM and subaortic obstruction with relatively limited leaflet motion, absence of a sharp bend, and septal contact involving more substantial portions of the anterior leaflet and contiguous chordae ("atypical" SAM); mitral-septal apposition was effected in large measure by posterior ventricular septal motion. This pattern of SAM was invariably associated with a more diffuse pattern of fibrous thickening.

CONCLUSIONS

Patients with obstructive HCM show patterns of mitral valve SAM that are diverse and determined largely by the interrelation of left ventricular outflow tract geometry, the size and mobility of the mitral leaflets, and the presence and distribution of fibrous thickening.
The cardioprotective effects of ischemic 'preconditioning' are not mediated by adenosine receptors in rat hearts.
Authors: Li Y , Kloner R A
Published: June 2012

BACKGROUND

Adenosine receptor activation has been proposed to explain the cardioprotective effect of ischemic preconditioning in rabbit hearts. We tested this hypothesis in a rat model by assessing whether administration of an adenosine antagonist could block the protective effect of preconditioning and whether adenosine is able to reduce infarct size in rat hearts when given before sustained coronary occlusion.

METHODS AND RESULTS

We assessed the effects of the adenosine antagonist 8-(p-sulfophenyl)theophylline (SPT) and adenosine on myocardial infarct size and the incidence of ventricular arrhythmias in five groups of rats: control (nonpreconditioned)+vehicle, control+SPT, preconditioned+vehicle, preconditioned+SPT, and control (nonpreconditioned)+adenosine. All rats underwent 90 minutes of coronary artery occlusion followed by 4 hours of reperfusion while preconditioned rats underwent three 3-minute episodes of ischemia, each separated by 5 minutes of reperfusion before sustained occlusion. The area at risk was determined by intravascular injection of blue dye during coronary artery occlusion, and infarct size was determined by incubation of heart slices in triphenyltetrazolium chloride. In the nonpreconditioned control rats receiving vehicle, myocardial infarct size expressed as a percentage of the area at risk averaged 55.2 +/- 4.8%. Pretreatment with SPT and adenosine had no effect on infarct size (52.2 +/- 3.1% and 52.6 +/- 3.8%, respectively) in the nonpreconditioned control animals compared with the control animals that received vehicle. Both the preconditioned+vehicle (16.4 +/- 4.3%) and the preconditioned+SPT (18.3 +/- 5.2%) groups had a significant reduction in infarct size (p < 0.01 versus control+vehicle, control+SPT, and control+adenosine), with no difference in infarct size between the two preconditioned groups. The incidence of ventricular tachycardia was significantly decreased in both the preconditioned+vehicle (10%, p < 0.05) and the preconditioned+SPT (25.0%, p < 0.05) groups when compared with the control+vehicle (100%), control+SPT (100%), and control+adenosine groups (100%). There was, however, no significant difference in the incidence of ventricular tachycardia between the preconditioned+vehicle and the preconditioned+SPT groups.

CONCLUSIONS

Because the adenosine antagonist SPT failed to abolish the cardioprotective effects of preconditioning and intravenous adenosine was unable to protect the hearts, it is unlikely that the mechanism of preconditioning is mediated by adenosine receptors in the rat model.
Reflex sympathoexcitation by cardiac sympathetic afferents during myocardial ischemia. Role of adenosine.
Authors: Thames M D , Kinugawa T , Dibner-Dunlap M E
Published: June 2012

BACKGROUND

Stimulation of cardiac sympathetic afferents during myocardial ischemia has been attributed to bradykinin released from the ischemic myocardium. Recent data from human studies suggest that adenosine may serve as this mediator. Our experiments were done to determine whether reflex sympathoexcitatory responses to activation of cardiac sympathetic afferents during myocardial ischemia could be inhibited by blockade of adenosine receptors and augmented by increasing the local concentrations of adenosine in the ischemic myocardium.

METHODS AND RESULTS

Experiments were done in 29 anesthetized dogs with bilateral vagotomy and carotid sinus denervation. Activation of cardiac sympathetic afferent fibers was induced by occlusion of the left anterior descending coronary artery (LAD) combined with rapid atrial pacing (pacing rate, 200 beats per minute). LAD occlusion plus rapid atrial pacing increased renal sympathetic nerve activity by 20 +/- 4% before but by only 7 +/- 1% after administration of aminophylline (100 mg i.v.), an adenosine receptor antagonist. In contrast, LAD occlusion during rapid atrial pacing increased renal sympathetic nerve activity by 18 +/- 8% before and 61 +/- 15% after treatment with dipyridamole (0.57 mg/kg i.v.), an inhibitor of adenosine reuptake. In a separate group of dogs, LAD occlusion during rapid atrial pacing increased renal sympathetic nerve activity similarly before and after sham treatment.

CONCLUSIONS

These data suggest that adenosine released during myocardial ischemia activates cardiac sympathetic afferents to cause reflex sympathoexcitation. These findings are consistent with observations made in humans that suggest that adenosine is the mediator of the sensation of angina pectoris, which also results from stimulation of cardiac sympathetic afferents.
Insulin-like growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytes.
Authors: Ito H , Hiroe M , Hirata Y , Tsujino M , Adachi S , Shichiri M , Koike A , Nogami A , Marumo F
Published: June 2012

BACKGROUND

Cardiac hypertrophy is commonly observed in acromegalic patients, in whom serum insulin-like growth factor-I (IGF-I) levels are elevated. In the present study, we examined whether IGF-I induces hypertrophy in cultured neonatal rat cardiomyocytes through its specific receptor and whether IGF binding protein-3 (IGFBP-3), which is a major circulating carrier protein for IGF-I, inhibits IGF-I-induced cardiac hypertrophy in vitro.

METHODS AND RESULTS

Because the response of cardiac hypertrophy is characterized by the induction of expression for muscle-specific genes, the effect of IGF-I on steady-state levels of mRNA for myosin light chain-2 (MLC-2) and troponin I and for skeletal and cardiac alpha-actin isoforms was evaluated by Northern blot analysis. IGF-I (10(-7) M) increased mRNA levels for MLC-2 and troponin I as early as 60 minutes with maximum levels by 6 hours, which were maintained for as long as 24 hours. IGF-I (10(-7) M) also increased transcripts for skeletal alpha-actin but not for cardiac alpha-actin. The cell size as evaluated morphometrically was almost doubled after 48-hour treatment with IGF-I. IGF-I induction of protein synthesis was dose dependent (10(-10) to 10(-7) M) with a maximal 2.2-fold increase seen at 10(-8) M. In contrast to the hypertrophic effect of IGF-I, growth hormone affected neither protein synthesis nor expression for muscle-specific genes. Binding study using 125I-IGF-I revealed the presence of specific binding sites for IGF-I in rat cardiomyocytes. IGFBP-3 induced a dose-dependent inhibition of protein synthesis stimulated by IGF-I; IGFBP-3 (10(-7) M) completely inhibited the [3H]leucine uptake stimulated by IGF-I (10(-8) M). IGFBP-3 similarly inhibited the IGF-I-stimulated gene expressions for MLC-2 and troponin I.

CONCLUSIONS

These results suggest that IGF-I directly causes cardiac hypertrophy and that its effect can be blocked by IGFBP-3.
Factors contributing to increased vascular fibrinolytic activity in mongrel dogs.
Authors: Lang I M , Marsh J J , Konopka R G , Olman M A , Binder B R , Moser K M , Schleef R R
Published: June 2012

BACKGROUND

Numerous investigators have observed that pulmonary emboli are rapidly lysed in a canine model system. This study was undertaken to delineate the unique mechanism that accounts for the rapid dissolution of pulmonary emboli in mongrel dogs.

METHODS AND RESULTS

Canine plasminogen activator (PA) activity (2.6 +/- 1.1 IU/mL acidified platelet-poor plasma [PPP], < 0.3 IU/mL acidified whole blood serum [WBS], mean +/- SD; n = 6) and PA inhibitor activity (6.1 +/- 2.6 U/mL PPP, 35.4 +/- 7.8 U/mL WBS; n = 6) were determined in standard plasminogen-based chromogenic assays. Analysis of canine PPP, WBS, platelet lysates, and primary canine endothelial cell (EC) cultures by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fibrin autography revealed a plasminogen-dependent lytic zone at 45-kd relative molecular mass that was shown to be related to urokinase-type PA (u-PA) by its selective inhibition through amiloride. Analysis of canine platelets on standard 125I fibrin plate assays revealed a net fibrinolytic activity. In a clot lysis assay system, canine platelets were able to stimulate fibrinolysis when layered on the outside of fibrin clots containing autologous PPP. Moreover, net fibrinolytic activity of primary canine pulmonary artery endothelial cells was higher than the activities expressed by canine aortic or carotid artery endothelial cells.

CONCLUSIONS

Rapid lysis of pulmonary emboli in mongrel dogs appears to be a result of 1) the high u-PA activity in canine PPP and 2) the predominant association of u-PA activity with canine platelets and canine pulmonary artery endothelial cells.
Symptoms, adverse effects, and complications associated with dobutamine stress echocardiography. Experience in 1118 patients.
Authors: Mertes H , Sawada S G , Ryan T , Segar D S , Kovacs R , Foltz J , Feigenbaum H
Published: June 2012

BACKGROUND

The use of dobutamine stress echocardiography for the evaluation of coronary artery disease is rapidly expanding. New applications of the technique are being investigated in a wide variety of patients including those with advanced coronary artery disease. Despite its widespread use, the safety of dobutamine stress echocardiography has not been sufficiently documented.

METHODS AND RESULTS

A consecutive series of 1118 patients undergoing dobutamine stress echocardiography for evaluation of known or suspected coronary artery disease form the basis of this report. Dobutamine stress testing was performed for evaluation of chest pain, risk assessment before noncardiac surgery, after recent myocardial infarction, or as a part of ongoing research protocols. Over the study period, the maximal dose of dobutamine used was increased from 30 to 50 micrograms/kg per minute, and atropine was used in 420 (37%) patients. There were no occurrences of death, myocardial infarction, or episodes of sustained ventricular tachycardia as a result of dobutamine stress testing. The major reasons for test termination were achievement of target heart rate in 583 patients (52.1%), maximum dose in 255 (22.8%), and angina pectoris in 142 (13%). The test was terminated in 36 (3%) patients because of noncardiac side effects including nausea, anxiety, headache, tremor, and urgency. Angina pectoris occurred in 216 (19.3%) patients. Sublingual nitroglycerin, a short-acting beta-blocker, or both types of medication were administered in 80 of these patients for relief of angina pectoris. None required intravenous nitroglycerin. A total of 736 (65%) patients had stable sinus rhythm throughout the test. The most common arrhythmias were frequent premature ventricular complexes (six or more per minute) in 172 patients (15%), and frequent premature atrial complexes in 86 (8%). There were 40 patients with nonsustained ventricular tachycardia. None had symptoms associated with the tachycardia, and only one received specific pharmacological treatment to prevent recurrence of the arrhythmia after the test was terminated. The patients who were evaluated after recent myocardial infarction and those who received atropine did not have a higher frequency of ventricular tachycardia compared with those without recent infarction and those not receiving atropine.

CONCLUSIONS

Dobutamine stress echocardiography was safely performed using supplemental atropine and an aggressive dosing protocol. Noncardiac side effects were usually minor. Arrhythmias were well tolerated and rarely required treatment. In this study, serious complications from myocardial ischemia did not occur. Symptomatic ischemia was effectively treated with test termination, sublingual nitroglycerin, or short-acting beta-blockers.
Relation between upper limit of vulnerability and defibrillation threshold in humans.
Authors: Chen P S , Feld G K , Kriett J M , Mower M M , Tarazi R Y , Fleck R P , Swerdlow C D , Gang E S , Kass R M
Published: June 2012

BACKGROUND

In the canine model, an upper limit of shock strength exists that can induce ventricular fibrillation during the vulnerable period of the cardiac cycle. This shock strength (the upper limit of vulnerability) closely correlates with the defibrillation threshold and supports the "upper limit of vulnerability" hypothesis of defibrillation. It is not known whether an upper limit of vulnerability exists in humans or whether this limit correlates with the defibrillation threshold.

METHODS AND RESULTS

In 13 patients undergoing implantable cardioverter-defibrillator implantation, the shock strengths associated with a 50% probability of reaching the upper limit of vulnerability (ULV50) and a 50% probability of reaching the defibrillation threshold (DFT50) were determined by the up-down algorithm. The ULV50 was determined only for the mid-upslope of the positive T waves and for the mid-downslope of the negative T waves. No major complications occurred during surgery. An upper limit of vulnerability was demonstrated in each patient. The ULV50 was 300 +/- 138 V or 6.8 +/- 5.8 J, which was significantly lower than the DFT50 of 347 +/- 167 V (p = 0.038) or 9.1 +/- 7.3 J (p = 0.013). The correlation between the ULV50 and the DFT50 was significant (r = 0.90, p < 0.001 for voltage; r = 0.93, p < 0.001 for energy).

CONCLUSIONS

An upper limit of vulnerability is present in humans. There is a significant correlation between the ULV50 and the DFT50, and the ULV50 is significantly lower than the DFT50.
Shear stress elevates endothelial cGMP. Role of a potassium channel and G protein coupling.
Authors: Ohno M , Gibbons G H , Dzau V J , Cooke J P
Published: June 2012

BACKGROUND

The endothelium acts as the sensor of shear stress and as the mediator of flow-induced changes in vessel tone and structure. The purpose of this study was to delineate the signal transduction pathway of flow-induced release of endothelium-derived relaxing factor (EDRF).

METHODS AND RESULTS

We used a shear stress apparatus (a modified cone-plate viscometer) to expose cultured endothelial cells to a well-defined laminar fluid flow. Confluent bovine aortic endothelial cells (BAECs) were subjected to varying levels of shear stress, and intracellular cyclic GMP (cGMP) in the BAECs was measured by radioimmunoassay. After 60 seconds of laminar fluid flow, BAEC cGMP increased by 300% from basal levels (from 0.54 to 1.70 pmol/mg protein, P < 0.05). The elevation in intracellular cGMP was proportional to the intensity of shear stress within a physiological range up to 40 dynes/cm2. This increase in cGMP was abrogated by L-N-methyl-arginine (the competitive antagonist of nitric oxide [NO] synthase), indicating that the flow-induced activation of soluble guanylate cyclase was mediated by autocrine NO production. Furthermore, a potassium channel antagonist, tetraethylammonium ion (TEA [3 mmol/L]) and a G(i) or G(o) protein inhibitor, pertussis toxin (100 ng/mL) also blocked the flow-induced increase in cGMP. By contrast, calcium ionophore or atrial natriuretic peptide caused elevations of cGMP that were not affected by TEA or pertussis toxin.

CONCLUSIONS

These findings indicate that shear stress elevates endothelial cGMP via an NO-dependent mechanism. The effect of shear stress is mediated by a unique signal transduction pathway that is coupled to a pertussis toxin-sensitive G protein and that requires the activity of an endothelial potassium channel.
Lisinopril lowers cardiac adrenergic drive and increases beta-receptor density in the failing human heart.
Authors: Gilbert E M , Sandoval A , Larrabee P , Renlund D G , O'Connell J B , Bristow M R
Published: June 2012

BACKGROUND

In subjects with heart failure, angiotensin converting enzyme inhibitors exhibit mild systemic antiadrenergic effects, as deduced from treatment-related lowering of systemic venous norepinephrine levels. The effects of angiotensin converting enzyme inhibitors on cardiac adrenergic drive in subjects with heart failure has not previously been investigated.

METHODS AND RESULTS

In a placebo-controlled, double-blind crossover study of 14 patients, we measured cardiac and systemic adrenergic drive, myocardial and lymphocyte beta-adrenergic receptors, and hemodynamic changes at baseline and after 12 weeks of therapy. Relative to placebo, lisinopril therapy was associated with only minimal, statistically insignificant changes in hemodynamics, a significant increase in myocardial beta-receptor density, no significant (P < .05) changes in cardiac or systemic adrenergic drive, and no detectable change in lymphocyte beta-receptor density. When subjects were rank ordered into groups with the highest and lowest coronary sinus norepinephrine levels, those with the highest norepinephrine levels exhibited significant decreases in central venous norepinephrine, coronary sinus norepinephrine, and an increase in myocardial beta-receptor density relative to changes in placebo or relative to baseline values. Subjects with lower cardiac adrenergic drive exhibited no significant changes in coronary sinus or systemic norepinephrine levels or in myocardial beta-receptor density.

CONCLUSIONS

The angiotensin converting enzyme inhibitor lisinopril lowered cardiac adrenergic drive and increased beta-receptor density in subjects with increased cardiac adrenergic drive but had no effects on these parameters in subjects with normal cardiac adrenergic drive. These data suggest that cardiac antiadrenergic properties contribute to the efficacy of angiotensin converting enzyme inhibitor in subjects with heart failure.
Physiology of blood flow during cardiopulmonary resuscitation. A transesophageal echocardiographic study.
Authors: Redberg R F , Tucker K J , Cohen T J , Dutton J P , Callaham M L , Schiller N B
Published: June 2012

BACKGROUND

There are two competing theories of the mechanism of blood flow during cardiopulmonary resuscitation. The "cardiac pump" theory postulates that blood flows because the heart is squeezed between the sternum and the spine. The "thoracic pump" theory postulates that blood flows from the thorax because intrathoracic pressure exceeds extrathoracic vascular pressure and that flow is restricted to the venous-to-arterial direction because of venous valves that prevent retrograde flow at the thoracic inlet. To determine which mechanism is operative during actual cardiopulmonary resuscitation, 20 patients were imaged with transesophageal echocardiography during resuscitation.

METHODS AND RESULTS

Transesophageal two-dimensional and pulse Doppler echocardiography was begun within 7 minutes of initiation of cardiopulmonary resuscitation. In the 18 patients who could be analyzed, the mitral valve opened during the release phase (diastole) and closed during the compression phase (systole) of cardiopulmonary resuscitation. Mitral velocity-time integral measured 8 +/- 3 cm during diastole. There was compression of right and left ventricular cavities with significant reduction in measured left ventricular volume during cardiopulmonary resuscitation. In five patients, mitral regurgitation was present.

CONCLUSIONS

Transesophageal echocardiography performed during actual cardiopulmonary resuscitation showing mitral valve opening during cardiac release, reduction of ventricular cavity size with compression, and atrioventricular regurgitation support the cardiac pump theory of cardiopulmonary resuscitation. This study demonstrates the feasibility and usefulness of transesophageal echocardiography during cardiopulmonary resuscitation.
Assessment of risk area during coronary occlusion and infarct size after reperfusion with myocardial contrast echocardiography using left and right atrial injections of contrast.
Authors: Villanueva F S , Glasheen W P , Sklenar J , Kaul S
Published: June 2012

BACKGROUND

Myocardial opacification during echocardiography has been demonstrated after left (LA) and right (RA) atrial injections of contrast, and microvascular damage with reduced blood flow and impaired flow reserve has been documented in necrotic myocardial tissue. Therefore, we hypothesized that because of its ability to depict capillary perfusion, myocardial contrast echocardiography (MCE) can be used to define risk area during coronary occlusion and infarct size after reperfusion with LA and RA injections of contrast in the presence of pharmacologically induced coronary hyperemia.

METHODS AND RESULTS

Eighteen open-chest anesthetized dogs with 3 to 6 hours of left anterior descending artery occlusion and 15 minutes of reflow were studied in the presence of either dipyridamole (0.56 mg/kg over a period of 4 minutes) or dobutamine (15 micrograms.kg-1.min-1). Technetium autoradiography was performed for risk area assessment; infarct size was measured with triphenyl tetrazolium chloride; and in 11 dogs, myocardial blood flow was measured with radiolabeled microspheres. A close linear relation was noted between the MCE defect size and autoradiographic risk area during coronary occlusion both during LA (y = 0.95x-0.25, r = .97, P < .001) and RA (y = 0.90x+0.98, r = .86, P < .001) injections of contrast. During reperfusion, the contrast defect size on MCE was always less transmural than during occlusion and correlated closely with infarct size during both LA (y = 1.07x-2.37, r = .98, P < .001) and RA (y = 1.02x-0.61, r = .95, P < .001) injections of contrast. In the 11 dogs in whom radiolabeled microsphere-derived blood flow was measured during reperfusion, an inverse relation was noted between infarct size and transmural blood flow (y = -1.12x+121, r = -.95, P = .001), implying that MCE defects after reperfusion indicate necrotic regions with reduced blood flow or impaired microvascular flow reserve. A close linear relation (y = 0.79x-0.001, r = .98, P < .001) was also noted between endocardial/epicardial ratio of background-subtracted peak video intensity on MCE and endocardial/epicardial blood flow ratio in the eight dogs with infarction who underwent this measurement after reperfusion.

CONCLUSIONS

MCE performed with LA and RA injections of contrast in the presence of pharmacologically induced coronary hyperemia can be used to determine, in vivo, the risk area during coronary occlusion and infarct size after reperfusion. These results could have important implications in this era of myocardial reperfusion.
The effect of porous infusion balloon-delivered angiopeptin on myointimal hyperplasia after balloon injury in the rabbit.
Authors: Hong M K , Bhatti T , Matthews B J , Stark K S , Cathapermal S S , Foegh M L , Ramwell P W , Kent K M
Published: June 2012

BACKGROUND

Angiopeptin, a synthetic somatostatin analogue, reduces myointimal hyperplasia after experimental balloon angioplasty when given subcutaneously. The feasibility and efficacy of a single dose of angiopeptin delivered locally via the Wolinsky porous balloon on myointimal hyperplasia were studied.

METHODS AND RESULTS

Three rabbits received 125I-angiopeptin in the mid abdominal aorta via the Wolinsky balloon at 5 atm for 1 minute after balloon injury. Thirty minutes later, autoradiography demonstrated radioactivity in the media and the adventitia. Forty rabbits were divided equally into one control group receiving saline and three angiopeptin groups receiving 1, 10, or 100 micrograms/mL of angiopeptin delivered locally at 5 atm for 1 minute via the Wolinsky balloon into the mid abdominal aorta after balloon injury of the entire abdominal aorta. On day 21, the abdominal aortas were fixed in situ and harvested. There was no statistical difference in the amount of myointimal hyperplasia in the locally treated aorta in the angiopeptin groups compared with the control group. However, in the lower abdominal aorta, where balloon injury without local delivery was performed, there was a significant reduction of myointimal hyperplasia in the highest-concentration angiopeptin group (P < .001 versus the control group). Electron microscopy showed that the control animals had a pseudointima of smooth muscle cells throughout the aorta, whereas in all the angiopeptin-treated animals, endothelial cells were present at both locations.

CONCLUSIONS

Angiopeptin can be delivered intramurally via the Wolinsky porous balloon and reduces myointimal hyperplasia only in the area distal to the local drug delivery site (downstream effect), possibly by healing the injured endothelium, by transport via the vasa vasora, and/or by systemic effect.
Receptor-mediated cardioprotective effects of endogenous adenosine are exerted primarily during reperfusion after coronary occlusion in the rabbit.
Authors: Zhao Z Q , McGee S , Nakanishi K , Toombs C F , Johnston W E , Ashar M S , Vinten-Johansen J
Published: June 2012

BACKGROUND

We hypothesized that: (1) endogenous adenosine released during ischemia/reperfusion reduces infarct size and preserves postischemic myocardial blood flow by receptor-mediated mechanisms and (2) this cardioprotection is exerted predominantly during reperfusion.

METHODS AND RESULTS

Sixty-one anesthetized open-chest rabbits subjected to 30 minutes of coronary occlusion and 120 minutes of reperfusion were randomized to six groups: group 1, saline (Vehicle) (n = 10) to allow receptor interaction of endogenous adenosine (Ado) during ischemia/reperfusion; group 2, Ado-receptor blockade during both ischemia and reperfusion with intravenous 8-p-sulfophenyltheophyl-line (10 mg/kg) (SPTIR, n = 10); group 3, Ado-receptor blockade in multiple doses during both ischemia and reperfusion (MSPTIR, n = 11); group 4, blockade during reperfusion (SPTR, n = 10); group 5, blockade during reperfusion with PD115,199 (6 mg/kg) (PDR, n = 10); and group 6, blockade after 30 minutes of reperfusion (SPT30R, n = 10) to allow adenosine receptor interaction during early reperfusion. Transmural myocardial blood flow in the area at risk (Ar) (15-microns radiolabeled microspheres) was reduced by 96.7% in all groups, from 137.9 +/- 15.5 to 4.5 +/- 1.4 mL.min-1 x 100 g-1 (P < .001). MSPTIR, SPTIR, and SPTR significantly attenuated reactive hyperemia at 15 minutes of reperfusion (144 +/- 18, 141 +/- 22, and 144 +/- 20 mL.min-1 x 100 g-1, respectively) compared with Vehicle (257 +/- 40 mL.min-1 x 100 g-1, P < .05). This attenuation was more pronounced in the necrotic zone than in the nonnecrotic zone. Reactive hyperemia at 15 minutes of reperfusion in SPT30R group was comparable to the Vehicle group. At 120 minutes of reperfusion, blood flow in Ar was significantly less in MSPTIR (77 +/- 10), SPTIR (82 +/- 9), and SPTR (80 +/- 11) compared with Vehicle (140 +/- 12) and SPT30R (105 +/- 24 mL.min-1 x 100 g-1). Infarct size (by triphenyltetrazolium chloride), expressed as a percent of Ar, was largest in the multiple-dose group with blockade during both ischemia and reperfusion (MSPTIR, 51.9 +/- 2.3%) and was significantly increased also in single-dose SPTIR (39.1 +/- 2.2%) compared with 25.7 +/- 1.7% in the Vehicle group (P < .05). Ado-receptor blockade only during reperfusion was associated with 14% smaller infarct size in the SPTR group than the MSPTIR group (P < .05). In contrast, Ado-receptor blockade after 30 minutes of reperfusion (SPT30R) did not increase infarct size (27.9 +/- 2.2%), which was comparable to infarct size in the Vehicle group.

CONCLUSIONS

We conclude that: (1) endogenous adenosine released from the myocardium during ischemia/reperfusion reduces infarct size by receptor-mediated mechanisms and (2) Ado-mediated cardioprotection is most pronounced during the early phase of reperfusion.
Circulating beta-atrial natriuretic factor in congestive heart failure in humans.
Authors: Wei C M , Kao P C , Lin J T , Heublein D M , Schaff H V , Burnett J C
Published: June 2012

BACKGROUND

beta-Atrial natriuretic factor (beta-ANF) is an antiparallel dimer of alpha-ANF (alpha-ANF) with diminished cyclic GMP generation in vitro. To date, the presence of beta-ANF in the circulation of humans with severe congestive heart failure (CHF) remains controversial. The current study was designed to determine the presence and magnitude of circulating beta-ANF in severe CHF, to correlate plasma beta-ANF with the degree of ventricular dysfunction, and to investigate the role of human plasma and atrial tissue in the degradation of beta-ANF.

METHODS AND RESULTS

Venous plasma samples were obtained from patients (n = 12) with severe CHF and normal volunteers (n = 8). Total plasma ANF was measured by radioimmunoassay. alpha-ANF and beta-ANF in nonextracted plasma were separated by gel filtration chromatography using a P-6 column. Right atrial tissue samples (n = 5) were collected from a different group of patients at the time of open-heart surgery. 125I beta-ANF and I125 ANF were incubated with atrial tissue or plasma. The corresponding peak areas of beta-ANF were determined by Tamaya Digital Planimeter. beta-ANF represented 61% of total plasma ANF in CHF patients and was not detected in normal human plasma. The elevation of beta-ANF correlated with the severity of ventricular dysfunction. Thirty percent of beta-ANF and 100% alpha-ANF were converted to smaller peptide fragments in atrial tissue no conversion in plasma.

CONCLUSIONS

beta-ANF is the principal form of circulating ANF in patients with severe CHF and correlates with the degree of left ventricular dysfunction. beta-ANF is not generated from alpha-ANF and may be degraded rapidly in atrial tissue to smaller peptide fragments that do not occur in plasma. As beta-ANF is reported to have reduced biological action, the current studies may support the conclusion that the ANF system in CHF has reduced functional activity despite increases in circulation concentrations.
Role of K+ATP channels in coronary vasodilation during exercise.
Authors: Duncker D J , Van Zon N S , Altman J D , Pavek T J , Bache R J
Published: June 2012

BACKGROUND

The mechanism of metabolic regulation of coronary vascular tone is still unclear. Therefore, we examined the role of vascular smooth muscle K+ATP channels in regulating coronary blood flow under resting conditions, during increments in myocardial metabolic demand produced by treadmill exercise, and in response to a brief ischemic stimulus.

METHODS AND RESULTS

Ten chronically instrumented dogs were studied at rest and during a four-stage exercise protocol under control conditions and during intracoronary infusion of the K+ATP channel blocker glibenclamide at rates of 10 and 50 micrograms.kg-1 x min-1. Glibenclamide (50 micrograms.kg-1 x min-1) decreased coronary blood flow at rest from 51 +/- 4 to 42 +/- 6 mL/min (P < .05), decreased myocardial oxygen consumption from 5.70 +/- 0.31 to 4.11 +/- 0.56 mL O2/min (P < .05), and decreased systolic wall thickening from 21 +/- 3% to 12 +/- 3% (P < .05). The depression of systolic wall thickening produced by glibenclamide was reversed when coronary blood flow was restored to the control level with intracoronary nitroprusside, indicating a primary effect of glibenclamide on coronary flow during resting conditions. However, glibenclamide did not impair the increases of coronary blood flow, myocardial oxygen consumption, and systolic wall thickening that occurred during exercise. In eight resting awake dogs, 50 micrograms.kg-1 x min-1 glibenclamide decreased the peak reactive hyperemia blood flow rate following a 20-second coronary occlusion from 149 +/- 14 mL/min during control conditions to 111 +/- 15 mL/min (P < .05), decreased the duration of reactive hyperemia from 49 +/- 6 to 33 +/- 3 seconds (P < .05), and decreased reactive hyperemia excess flow from 33 +/- 5 to 20 +/- 4 mL (P < .05).

CONCLUSIONS

These data demonstrate that K+ATP channels modulate coronary vasomotor tone under resting conditions and contribute to coronary vasodilation during ischemia. However, the coronary vasculature retains the capacity to dilate in response to increases in oxygen demand produced by exercise when K+ATP channels are blocked.
Increased risk of coronary heart disease death in men with low total and low-density lipoprotein cholesterol in the Russian Lipid Research Clinics Prevalence Follow-up Study.
Authors: Shestov D B , Deev A D , Klimov A N , Davis C E , Tyroler H A
Published: June 2012

BACKGROUND

A continuously increasing risk of coronary heart disease with increasing levels of cholesterol has been reported by many observational and experimental studies. However, this type of association has not been observed in studies in the Russian Lipid Research Clinics.

METHODS AND RESULTS

Twelve-year coronary heart disease mortality among 40- to 59-year-old men was analyzed in the Moscow and St Petersburg examines in the Russian Lipid Research Clinics Program. The baseline survey examined 6431 men fasting and free of prevalent coronary heart disease. Lipids and lipoproteins, blood pressure, body mass, education level, alcohol intake, and smoking history were obtained. Mortality follow-up was based on contacts with participants or their relatives or neighbors. Coronary heart disease mortality was analyzed based on risk factor levels and was further divided into rapid and nonrapid deaths. A J-shaped cholesterol-coronary heart disease risk function was present for both total and low-density lipoprotein cholesterol. Further examination showed hypocholesterolemic men to have lower low-density and higher high-density lipoprotein cholesterol, higher alcohol consumption, leaner body mass, and less education than men with normal or high cholesterol levels. When education level was considered, the J-shaped risk function was present only among men with less than a high school education. When deaths were classified into rapid (less than 24 hours after onset of symptoms) and nonrapid, the J-shaped risk function was restricted to rapid deaths.

CONCLUSIONS

The results of disclose a sizeable subset of hypocholesterolemics in this population at increased risk of cardiac death associated with lifestyle characteristics.
Blunted nocturnal fall in blood pressure in hypertensive women with future cardiovascular morbid events.
Authors: Verdecchia P , Schillaci G , Gatteschi C , Zampi I , Battistelli M , Bartoccini C , Porcellati C
Published: June 2012

BACKGROUND

In essential hypertension, a blunted or absent nocturnal fall in blood pressure (BP) may be associated with increased target organ damage. In this case-control study, we tested the hypothesis that an association exists between a blunted or absent nocturnal fall in BP and future cardiovascular morbid events in patients with essential hypertension.

METHODS AND RESULTS

Case subjects were 32 hypertensive patients with a first fatal or nonfatal major cardiovascular event who had off-therapy ambulatory BP monitoring 1 to 5 years earlier in the context of a registry of morbidity and mortality in hypertensive patients. Control subjects were 49 hypertensive patients free from cardiovascular events. The groups were matched with regard to date of baseline ambulatory BP monitoring, age, sex, clinic systolic and diastolic BP, and daytime ambulatory systolic and diastolic BP. At their baseline evaluation, cases and controls did not differ, in either sex, with respect to clinic BP (men, 164/100 vs 162/99 mmHg; women, 178/96 vs 180/93 mmHg), mean daytime ambulatory BP (men, 151/94 vs 147/95 mm Hg; women, 156/90 vs 158/89 mm Hg), age (men, 55 vs 56 years; women, 69 vs 68 years), sex, body weight, serum cholesterol, known duration and family history of hypertension, smoking habits, renal function, or prevalence of diabetes. Echocardiographic left ventricular mass, determined in a subset of patients, was greater in cases than in controls in men (145 vs 115 g/m2, P = .038) and women (137 vs 102 g/m2, P = .032). The time interval between baseline ambulatory BP monitoring and subsequent cardiovascular event (cases: mean, 2.1 years) or last contact with our center (controls: mean, 2.5 years) did not differ between the groups. In the baseline ambulatory BP profile, the nocturnal reductions of systolic and diastolic BP in men were 9% and 11%, respectively, in cases vs 9% and 12% in controls (all P = NS), whereas in women they were 3% and 8% in cases vs 11% and 16% in controls (P = .002/.004).

CONCLUSIONS

This retrospective case-control study suggests an association between the reduction or absence of the usual nocturnal fall in BP and future cardiovascular morbid events in white women with essential hypertension.
Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease.
Authors: Kang S S , Passen E L , Ruggie N , Wong P W , Sora H
Published: June 2012

BACKGROUND

To determine whether or not a moderate genetic defect of homocysteine metabolism is associated with the development of coronary artery disease, we studied the prevalence of thermolabile methylenetetrahydrofolate reductase, which is probably the most common genetic defect of homocysteine metabolism.

METHODS AND RESULTS

Three hundred thirty-nine subjects who underwent coronary angiography were classified into three groups: (1) patients with severe coronary artery stenosis (> or = 70% occlusion in one or more coronary arteries or > or = 50% occlusion in the left main coronary artery), (2) patients with mild to moderate coronary artery stenosis (< 70% occlusion in one or more coronary arteries or < 50% occlusion in the left main coronary artery), and (3) patients with non-coronary heart disease or noncardiac chest pain (nonstenotic coronary arteries). The thermolability of methylenetetrahydrofolate reductase was prospectively determined in all subjects. Plasma homocyst(e)ine levels were then measured in those with thermolabile methylenetetrahydrofolate reductase. The traditional risk factors for coronary artery disease were thereafter ascertained by chart review of all subjects. The prevalence of thermolabile methylenetetrahydrofolate reductase was 18.1% in group 1, 13.4% in group 2, and 7.9% in group 3. There was a significant difference between the prevalence of thermolabile methylenetetrahydrofolate reductase in groups 1 and 3 (P < .04). All individuals with thermolabile methylenetetrahydrofolate reductase irrespective of their clinical grouping had higher plasma homocyst(e)ine levels than normal (group 1, 14.86 +/- 5.85; group 2, 15.36 +/- 5.70; group 3, 13.39 +/- 3.80; normal, 8.50 +/- 2.8 nmol/mL). Nonetheless, there was no statistically significant difference in the plasma homocyst(e)ine concentrations of these patients with or without coronary artery stenosis. Using discriminant function analysis, thermolabile methylenetetrahydrofolate reductase was predictive of angiographically proven coronary artery stenosis. The traditional risk factors--age, sex, diabetes, smoking, hypercholesterolemia, and hypertension--were not significantly associated with the presence of thermolabile methylenetetrahydrofolate reductase.

CONCLUSIONS

Thermolabile methylenetetrahydrofolate reductase is a risk factor for coronary artery disease and is unrelated to other risk factors.
Effect of strenuous exercise on platelet activation state and reactivity.
Authors: Kestin A S , Ellis P A , Barnard M R , Errichetti A , Rosner B A , Michelson A D
Published: June 2012

BACKGROUND

It has been hypothesized that platelets are activated, or made more activatible, by strenuous exercise and that these changes may play a role in the genesis of exercise-induced coronary ischemia. Previous studies have yielded conflicting results but have used assays (eg, platelet aggregation, plasma platelet factor 4, and plasma beta-thromboglobulin) that are subject to methodological problems.

METHODS AND RESULTS

In the present study, a whole blood flow cytometric method was used to study the platelet activation state and reactivity of 12 physically active and 12 sedentary individuals before and after standardized treadmill exercise testing. The peptide gly-pro-arg-pro (GPRP) was included in this assay to prevent fibrin polymerization and platelet aggregation, thus allowing the measurement of the reactivity to thrombin of individual platelets in the physiological milieu of whole blood. A panel of fluorescent-labeled monoclonal antibodies was used to monitor activation-dependent platelet surface changes: downregulation of glycoprotein (GP) Ib (6D1) and upregulation of GMP-140 (S12), the GPIIb-IIIa complex (PAC1), and GPIV (OKM5). In samples obtained before exercise, platelets not exposed to thrombin showed no evidence of in vitro activation. In the sedentary subjects, exercise caused a consistent and significant augmentation of the platelet activation state and reactivity as judged by the binding of 6D1 in the presence of thrombin 0.05 U/mL (P < .001), 0.005 U/mL (P = .001), and 0 U/mL (P = .004) and by the binding of OKM5 in the presence of thrombin 0.05 U/mL (P < .001), 0.005 U/mL (P = .029), and 0 U/mL (P = .035). Exercise increased the binding of PAC1 at only a single thrombin concentration (0.005 U/mL, P = .027) and did not alter the binding of S12 at any thrombin concentration. In contrast, in the physically active subjects, exercise failed to cause a consistent alteration in either platelet activation state or platelet reactivity. No significant differences were found between the 12 male and 12 female volunteers.

CONCLUSIONS

Strenuous exercise in sedentary subjects but not physically active subjects resulted in both platelet activation and platelet hyperreactivity. These changes were more readily detected with monoclonal antibodies directed against GPIb (6D1) and, to a lesser extent, GPIV (OKM5) rather than those directed against the GPIIb-IIIa complex (PAC1) and GMP-140 (S12). Platelet activation by thrombin, generally regarded as the most physiologically important agonist, can be studied in whole blood in a clinical setting through the use of the peptide GPRP.
Abnormalities of sodium handling and of cardiovascular adaptations during high salt diet in patients with mild heart failure.
Authors: Volpe M , Tritto C , DeLuca N , Rubattu S , Rao M A , Lamenza F , Mirante A , Enea I , Rendina V , Mele A F
Published: June 2012

BACKGROUND

Sodium retention and hormonal activation are fundamental hallmarks in congestive heart failure. The present study was designed to assess the ability of patients with asymptomatic to mildly symptomatic heart failure and no signs or symptoms of congestion to excrete ingested sodium and to identify possible early abnormalities of hormonal and hemodynamic mechanisms related to sodium handling.

METHODS AND RESULTS

The effects of a high salt diet (250 mEq/day for 6 days) on hemodynamics, salt-regulating hormones, and renal excretory response were investigated in a balanced study in 12 untreated patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (NYHA class I-II, ejection fraction < 50%) (HF) and in 12 normal subjects, who had been previously maintained a 100 mEq/day NaCl diet. In normal subjects, high salt diet was associated with significant increases of echocardiographically measured left ventricular end-diastolic volume, ejection fraction, and stroke volume (all P < .001) and with a reduction of total peripheral resistance (P < .001). In addition, plasma atrial natriuretic factor (ANF) levels increased (P < .05), and plasma renin activity and aldosterone concentrations fell (both P < .001) in normals in response to salt excess. In HF patients, both left ventricular end-diastolic and end-systolic volumes increased in response to high salt diet, whereas ejection fraction and stroke volume failed to increase, and total peripheral resistance did not change during high salt diet. In addition, plasma ANF levels did not rise in HF in response to salt loading, whereas plasma renin activity and aldosterone concentrations were as much suppressed as in normals. Although urinary sodium excretions were not significantly different in the two groups, there was a small but systematic reduction of daily sodium excretion in HF, which resulted in a significantly higher cumulative sodium balance in HF than in normals during the high salt diet period (P < .001).

CONCLUSIONS

These results show a reduced ability to excrete a sodium load and early abnormalities of cardiac and hemodynamic adaptations to salt excess in patients with mild heart failure and no signs or symptoms of congestion.
Induction of right ventricular hypertrophy with obstructing balloon catheter. Nonsurgical ventricular preparation for the arterial switch operation in simple transposition.
Authors: Katayama H , Krzeski R , Frantz E G , Ferreiro J I , Lucas C L , Ha B , Henry G W
Published: June 2012

BACKGROUND

Recently, a successful result with a rapid two-stage arterial switch operation (ASO) was reported for patients with transposition of the great arteries (TGA) with low left ventricular pressure. In this procedure, the interval between pulmonary arterial banding and ASO was approximately 1 week. This successful result indicates the possibility of a nonsurgical ventricular preparation procedure using an obstructing balloon catheter prior to ASO.

METHODS AND RESULTS

A 5F atrioseptostomy catheter was inserted directly into the main pulmonary artery in six lambs aged 20 to 38 days. After the chest was closed, the balloon was inflated twice a day for a period of 2 to 2.5 hours. This procedure was performed for 4 consecutive days. After the final inflation, the ratio of right ventricular weight to total ventricular weight was compared with that in an age-matched control group. After the final inflation, the peak systolic right ventricular pressure and the percentage of peak systolic right ventricular to peak systolic aortic pressure rose to 85.6 +/- 4.7 mm Hg (mean +/- 1 SD) and 79.6 +/- 8.6%, respectively. The percentages of the right ventricular weight to the total ventricular weight were significantly higher after the balloon inflation than those in the control group in terms of wet heart weight (29.5 +/- 1.2% versus 23.0 +/- 1.0%; P < .0001) and dry heart weight (27.0 +/- 2.0% versus 21.0 +/- 1.1%; P < .0001).

CONCLUSIONS

The myocardial mass in the right ventricle increased after 4 days of intermittently applied pressure overload. Nonsurgical preparation of the ventricle for ASO in TGA is feasible.