bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental changes in modulation of calcium currents of rabbit ventricular cells by phosphodiesterase inhibitors.
Authors: Akita T , Joyner R W , Lu C , Kumar R , Hartzell H C
Published: June 2012

BACKGROUND

We have previously shown major differences in beta-adrenergic and muscarinic modulation of L-type calcium currents (ICa) in newborn and adult rabbit heart. However, little is known about developmental changes in modulation of ICa by phosphodiesterases (PDEs), which also regulate intracellular cAMP concentration by its hydrolysis.

METHODS AND RESULTS

Enzymatically isolated adult and newborn (1- to 3-day-old) rabbit ventricular myocytes were used to study the effects of PDE inhibitors on ICa measured by the whole-cell patch-clamp method. 3-Isobutyl-1-methyl-xanthine (IBMX), a nonselective PDE inhibitor, increased ICa in a dose-dependent manner for both groups. The maximal effect of IBMX, expressed as percentage increase in ICa over control levels, was greater for newborn myocytes than for adult myocytes, but the effects of IBMX applied alone were observed only at concentrations > 10 mumol/L. The concomitant use of 0.1 mumol/L isoproterenol produced a significant potentiation of the IBMX effect on ICa, with a significant additive effect of IBMX in newborn myocytes even at 0.05 mumol/L IBMX. The concomitant use of a subthreshold concentration of IBMX (0.1 mumol/L) did not potentiate the dose dependence of adult ICa on isoproterenol but did markedly potentiate the dose dependence of newborn ICa on isoproterenol. The Emax and EC50 of isoproterenol in the presence of 0.1 mumol/L IBMX on newborn ICa were 235% and 8 nmol/L, respectively, whereas the Emax and EC50 of isoproterenol in the absence of IBMX on newborn ICa were 111% and 81 nmol/L, respectively. The addition of 50 mumol/L IBMX to 10 mumol/L isoproterenol markedly increased the newborn ICa density up to a level equivalent to that reached with 200 mumol/L cAMP in the pipette (14.9 +/- 1.2 versus 13.4 +/- 0.7 pA/pF). Our data suggest that the inhibition constant (Ki) of IBMX for inhibiting PDEs that participate in the regulation of ICa is much lower in newborn than in adult myocytes. Milrinone 1 mumol/L, a selective PDE III inhibitor, increased the 0.1 mumol/L isoproterenol-stimulated ICa of adult myocytes but had no significant additive effect for the 0.1 mumol/L isoproterenol-stimulated ICa of newborn myocytes. Rolipram 1 mumol/L, a selective PDE IV inhibitor, increased the 0.1 mumol/L isoproterenol-stimulated ICa for newborn myocytes but had no significant additive effect for the 0.1 mumol/L isoproterenol-stimulated ICa for adult myocytes.

CONCLUSIONS

These results suggest that the most important PDE isozyme for regulation of ICa of rabbit myocytes changes from PDE IV to PDE III during the postnatal period.
Coronary vasodilator reserve, pain perception, and sex in patients with syndrome X.
Authors: Rosen S D , Uren N G , Kaski J C , Tousoulis D , Davies G J , Camici P G
Published: June 2012

BACKGROUND

It remains unclear whether myocardial ischemia due to coronary microvascular dysfunction is the cause of chest pain in syndrome X (chest pain, ischemic-like stress ECG despite angiographically normal coronary arteries). To assess the function of the coronary microcirculation and its relation to pain perception, we measured myocardial blood flow (MBF) and coronary vasodilator reserve (CVR) in 29 patients with syndrome X and 20 matched normal control subjects.

METHODS AND RESULTS

MBF at rest and after intravenous dipyridamole (0.56 mg.kg-1 over 4 minutes) was measured using positron emission tomography with H2(15)O. CVR was calculated as MBFdipyridamole/MBFrest. ECG changes and chest pain after dipyridamole in syndrome X were compared with those in 35 patients with coronary artery disease (CAD). Resting and postdipyridamole MBFs were homogeneous throughout the left ventricle in syndrome X patients and control subjects. MBF was 1.05 (0.25), mean (SD) versus 1.00 (0.22) mL.min-1.g-1 (P = NS) at rest and 2.73 (0.81) versus 3.00 (1.00) mL.min-1.g-1 (P = NS) after dipyridamole in patients and control subjects, respectively. CVRs were 2.66 (0.76) and 3.06 (1.08) (P = NS) and after correction of resting MBF for rate-pressure product were 2.35 (0.83) and 2.34 (0.90) (P = NS) in patients and control subjects, respectively. Female syndrome X patients had higher resting MBF than males, at 1.18 (0.20) versus 0.88 (0.19) mL.min-1.g-1 (P < .001). Chest pain after dipyridamole occurred in syndrome X as frequently as in CAD (21/29 versus 22/35, P = NS).

CONCLUSIONS

When patients with syndrome X are compared with control subjects, no differences are found in MBF either at rest or after dipyridamole, despite syndrome X patients experiencing chest pain after dipyridamole to the same extent as patients with CAD. These findings, together with the absence of any relation among MBF, chest pain, and ECG changes under stress, cast further doubt on ischemia as the basis of the chest pain, at least in the majority of syndrome X patients.
Persistent activation of coagulation mechanism in unstable angina and myocardial infarction.
Authors: Merlini P A , Bauer K A , Oltrona L , Ardissino D , Cattaneo M , Belli C , Mannucci P M , Rosenberg R D
Published: June 2012

BACKGROUND

The blood coagulation system is activated in the acute phase of unstable angina and acute myocardial infarction. However, it remains unclear whether augmented function of the hemostatic mechanism serves only as a marker of the acute thrombotic episode or whether a hypercoagulable state persists for a prolonged period after clinical stabilization.

METHODS AND RESULTS

We prospectively measured the plasma concentrations of prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FPA) in consecutive patients presenting with unstable angina (n = 81) or acute myocardial infarction (n = 32), respectively. At 6 months, plasma determinations were repeated in patients experiencing an uneventful clinical course (unstable angina, n = 57; myocardial infarction, n = 23). We quantitated the plasma levels of F1 + 2 and FPA in control patients with stable angina (n = 37) or healthy individuals (n = 32) who were matched for age and sex. The median plasma concentrations of F1 + 2 and FPA are significantly higher in patients presenting with unstable angina (F1 + 2, 1.08 nmol/L; FPA, 2.4 nmol/L) or acute myocardial infarction (F1 + 2, 1.27 nmol/L; FPA, 3.55 nmol/L) compared with patients with stable angina (F1 + 2, 0.74 nmol/L; FPA, 1.3 nmol/L; P < .0001) or healthy individuals (F1 + 2, 0.71 nmol/L; FPA, 0.80 nmol/L; P < .0001). At 6 months, the median plasma levels of F1 + 2 in patients exhibiting an uneventful clinical course did not differ from values obtained at admission (unstable angina, 1.26 versus 1.07 nmol/L, P = NS; myocardial infarction, 1.22 versus 1.29 nmol/L, P = NS), whereas the median plasma levels of FPA in the same two subpopulations were significantly reduced (unstable angina, 1.1 versus 2.9 nmol/L, P = .0003; myocardial infarction, 1.1 versus 3.0 nmol/L; P = .0028).

CONCLUSIONS

During the acute phase of unstable angina and myocardial infarction, patients exhibit increased coagulation system activity. Over the next 6 months, patients with unstable angina or myocardial infarction experiencing an uneventful clinical course manifest a persistent hypercoagulable state with minimal generation of fibrin.
Intensive vascular training in stage IIb of peripheral arterial occlusive disease. The additive effects of intravenous prostaglandin E1 or intravenous pentoxifylline during training.
Authors: Scheffler P , de la Hamette D , Gross J , Mueller H , Schieffer H
Published: June 2012

In a randomized open study, the combination of either prostaglandin E1 (PGE1) or pentoxifylline with controlled vascular training was compared with vascular training alone in patients with peripheral arterial occlusive disease in stage IIb. Forty-four patients were randomly assigned to treatment either of intensive vascular training alone (n = 15) or in combination with either i.v. pentoxifylline (200 mg over 2 hours BID, n = 15) or PGE1 (40 micrograms over 2 hours BID, n = 14). The basic therapy was a well-defined routine for vascular training, which was identical for all groups. The duration of therapy was 4 weeks. In all three test groups, there was a significant increase in the walking distance. There was a 119% increase in symptom-free walking distance in the exercise-only group. In comparison with exercise alone, the additional administration of pentoxifylline produced no greater effect; the increase was 105%. In contrast, administration of PGE1 combined with exercise achieved a remarkable improvement of 604%. Between-group comparison revealed the significant superiority of treatment with PGE1 (P < .05). During the 1-year follow-up, there was a reduction in the walking performance in all groups, albeit of variable extent. In the exercise-only and the pentoxifylline groups, the maintained increase in walking distance was only 30% compared with baseline values before the beginning of therapy. In the PGE1 group, on the other hand, the maintained improvement was 149%. Nine of 14 patients were still in stage IIa of peripheral arterial occlusive disease 1 year after PGE1 therapy.
Three-dimensional left ventricular deformation in hypertrophic cardiomyopathy.
Authors: Young A A , Kramer C M , Ferrari V A , Axel L , Reichek N
Published: June 2012

BACKGROUND

In hypertrophic cardiomyopathy, ejection fraction is normal or increased, and force-length relations are reduced. However, three-dimensional (3D) motion and deformation in vivo have not been assessed in this condition. We have reconstructed the 3D motion of the left ventricle (LV) during systole in 7 patients with hypertrophic cardiomyopathy (HCM) and 12 normal volunteers by use of magnetic resonance tagging.

METHODS AND RESULTS

Transmural tagging stripes were automatically tracked to subpixel resolution with an active contour model. A 3D finite-element model was used to interpolate displacement information between short- and long-axis slices and register data on a regional basis. Displacement and strain data were averaged into septal, posterior, lateral, and anterior regions at basal, midventricular, and apical levels. Radial motion (toward the central long axis) decreased slightly in patients with HCM, whereas longitudinal displacement (parallel to the long axis) of the base toward the apex was markedly reduced: 7.5 +/- 2.5mm (SD) versus 12.5 +/- 2.0 mm, P < .001. Circumferential and longitudinal shortening were both reduced in the septum (P < .01 at all levels). The principal strain associated with 3D maximal contraction was slightly depressed in many regions, significantly in the basal septum (-0.18 +/- 0.05 versus -0.22 +/- 0.02, P < .05) and anterior (-0.20 +/- 0.05 versus -0.23 +/- 0.02, P < .05) walls. In contrast, LV torsion (twist of the apex about the long axis relative to the base) was greater in HCM patients (19.9 +/- 2.4 degrees versus 14.6 +/- 2.7 degrees, P < .01).

CONCLUSIONS

HCM patients had reduced 3D myocardial shortening on a regional basis; however, LV torsion was increased.
Transcatheter delivery of c-myc antisense oligomers reduces neointimal formation in a porcine model of coronary artery balloon injury.
Authors: Shi Y , Fard A , Galeo A , Hutchinson H G , Vermani P , Dodge G R , Hall D J , Shaheen F , Zalewski A
Published: June 2012

BACKGROUND

Smooth muscle cell proliferation and extracellular matrix accumulation are the principal mechanisms leading to vascular restenosis. We have previously demonstrated the growth-inhibitory effect of antisense oligomers targeting the c-myc proto-oncogene in human smooth muscle cells. The goal of this study was to investigate whether c-myc antisense oligomers reduce neointimal formation in balloon-denuded porcine coronary arteries.

METHODS AND RESULTS

First, type I collagen synthesis, which reflects synthetic function, was markedly reduced following c-myc antisense oligomers in porcine vascular smooth muscle cells independent of the growth inhibition. These effects in vitro provided the rationale for assessing c-myc antisense oligomers in the prevention of neointima in vivo. Second, the efficiency of single transcatheter delivery of oligomers into denuded porcine coronary arteries was determined. Despite rapid plasma clearance following local delivery, oligomers persisted at the site of injection for at least 3 days, exceeding by severalfold their concentration in peripheral organs. Third, morphometric analyses were carried out in balloon-denuded coronary arteries at 1 month after transcatheter c-myc antisense oligomer administration. Maximal neointimal area was reduced from 0.80 +/- 0.17 mm2 in the control group (n = 12) to 0.24 +/- 0.06 mm2 in the antisense-treated group (n = 13, P < .01). Likewise, a significant reduction in maximal neointimal thickness was observed in the antisense-treated group (P < .01). These changes in vascular remodeling following denuding injury resulted in an increase in residual lumen from 64 +/- 6% in the control group to 81 +/- 5% in the antisense-treated group (P < .05).

CONCLUSIONS

(1) Single transcatheter administration allowed for endoluminal delivery of oligomers to the site of coronary arterial injury. (2) C-myc antisense oligomers reduced the formation of neointima in denuded coronary arteries, implying a therapeutic potential of this approach for the prevention of coronary restenosis. (3) It is postulated that the c-myc proto-oncogene is involved in the process of vascular remodeling, regulating smooth muscle cell proliferation and extracellular matrix synthesis.
Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial.
Authors: Antman E M
Published: June 2012

BACKGROUND

The Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A trial compared the efficacy and safety of intravenous hirudin with heparin as adjunctive therapy to thrombolysis and aspirin in patients with acute myocardial infarction. The primary safety end point was the occurrence of major hemorrhage or anaphylaxis.

METHODS AND RESULTS

Based on experience in phase II trials, TIMI 9A used a hirudin bolus of 0.6 mg/kg followed by a fixed-dose 96-hour infusion of 0.2 mg/kg per hour. A modified weight-adjusted heparin regimen was used (5000-U bolus and infusion of 1000 U/h for patients < 80 kg or 1300 U/h for patients > or = 80 kg) with titration to a target activated partial thromboplastin time (aPTT) of 60 to 90 seconds. Because rates of hemorrhage in both treatment arms were higher than expected, randomization was suspended in TIMI 9A after 757 patients had been enrolled. Intracranial hemorrhage occurred in 1.7% of patients treated with hirudin and 1.9% of those treated with heparin (P = NS). Major spontaneous hemorrhage at a nonintracranial site occurred more frequently in hirudin--than in heparin-treated patients (7.0% versus 3.0%; P = .02), whereas major hemorrhage at instrumented sites was similar (5.2% in both hirudin and heparin groups). Patients who developed a major hemorrhage were older (P < .001) and had higher aPTT values, especially in the first 12 hours after thrombolysis (P = .001).

CONCLUSIONS

The rate of major spontaneous hemorrhage for both heparin and hirudin in TIMI 9A was higher than that seen in TIMI 5, TIMI 6, and GUSTO 1. This was possibly a result of high levels of anticoagulation at the doses of heparin and hirudin used, low previous estimates of the hemorrhage risk at the doses of hirudin used in TIMI 9A due to the relatively small number of patients receiving that dose in earlier studies, and enrollment of patients at higher risk of hemorrhage. Because a prolonged aPTT was associated with an increased risk of major hemorrhage in both heparin- and hirudin-treated patients, it now appears important to monitor aPTT on a regular basis when using either antithrombin to identify those patients who require downward adjustment of the infusion. TIMI 9B has therefore been configured with a lower hirudin bolus (0.1 mg/kg) and infusion (0.1 mg/kg per hour) and lower heparin infusion (1000 U/h without weight adjustment). Infusions of both antithrombins will be titrated to a target aPTT of 55 to 85 seconds.
Molecular cloning of human prostacyclin receptor cDNA and its gene expression in the cardiovascular system.
Authors: Nakagawa O , Tanaka I , Usui T , Harada M , Sasaki Y , Itoh H , Yoshimasa T , Namba T , Narumiya S , Nakao K
Published: June 2012

BACKGROUND

Prostacyclin elicits a potent vasodilation and inhibition of platelet aggregation through binding to its membrane receptor. The impairment of prostacyclin receptor activity is implicated in various human cardiovascular diseases. In the present study, we succeeded in the isolation and characterization of human prostacyclin receptor cDNA and elucidated its gene expression in human tissues.

METHODS AND RESULTS

We isolated a cDNA clone encoding the human prostacyclin receptor from a human lung cDNA library. The isolated cDNA clone encodes a 386-amino acid protein with seven putative transmembrane domains, which belongs to the G protein-coupled receptor superfamily. [3H]iloprost, a prostacyclin receptor agonist, specifically bound to the receptor transiently expressed in COS-7 cells. The binding was inhibited in the rank order of iloprost = cicaprost, another prostacyclin receptor agonist, > prostaglandin E1 (PGE1) > PGE2, PGF2 alpha, PGD2, STA2. In addition, iloprost dose-dependently stimulated cAMP generation in these COS-7 cells. These results are consistent with the characteristics of the human prostacyclin receptor. Northern blotting analysis on human tissues revealed that prostacyclin receptor mRNA is abundantly expressed in the aorta, lung, atrium, ventricle, and kidney.

CONCLUSIONS

We cloned human prostacyclin receptor cDNA and elucidated its abundant gene expression in the human cardiovascular system. The present study will lead to better understanding of the significance of prostacyclin in humans and further facilitate the clinical application of prostacyclin.
Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group.
Authors: Furberg C D , Adams H P , Applegate W B , Byington R P , Espeland M A , Hartwell T , Hunninghake D B , Lefkowitz D S , Probstfield J , Riley W A
Published: June 2012

BACKGROUND

HMG CoA reductase inhibitors (or statins), a new class of lipid-lowering compounds, have raised expectations for more widespread use than that of the older lipid-lowering drugs. Not only are they more effective in lowering LDL cholesterol, but they are better tolerated as well. No data exist concerning the effect of statins on early carotid atherosclerosis and clinical events in men and women who have moderately elevated LDL cholesterol levels but are free of symptomatic cardiovascular disease.

METHODS AND RESULTS

Lovastatin (20 to 40 mg/d) or its placebo was evaluated in a double-blind, randomized clinical trial with factorial design along with warfarin (1 mg/d) or its placebo. This report is limited to the lovastatin component of the trial. Daily aspirin (81 mg/d) was recommended for everyone. Enrollment included 919 asymptomatic men and women, 40 to 79 years old, with early carotid atherosclerosis as defined by B-mode ultrasonography and LDL cholesterol between the 60th and 90th percentiles. The 3-year change in mean maximum intimal-medial thickness (IMT) in 12 walls of the carotid arteries was the primary outcome; change in single maximum IMT and incidence of major cardiovascular events were secondary outcomes. LDL cholesterol fell 28%, from 156.6 mg/dL at baseline to 113.1 mg/dL at 6 months (P < .0001), in the lovastatin groups and was largely unchanged in the lovastatin-placebo groups. Among participants not on warfarin, regression of the mean maximum IMT was seen after 12 months in the lovastatin group compared with the placebo group; the 3-year difference was statistically significant (P = .001). A larger favorable effect of lovastatin was observed for the change in single maximum IMT but was not statistically significant (P = .12). Five lovastatin-treated participants suffered major cardiovascular events--coronary heart disease mortality, nonfatal myocardial infarction, or stroke--versus 14 in the lovastatin-placebo groups (P = .04). One lovastatin-treated participant died, compared with eight on lovastatin-placebo (P = .02).

CONCLUSIONS

In men and women with moderately elevated LDL cholesterol, lovastatin reverses progression of IMT in the carotid arteries and appears to reduce the risk of major cardiovascular events and mortality. Results from ongoing large-scale clinical trials may further establish the clinical benefit of statins.
Open infarct artery, late potentials, and other prognostic factors in patients after acute myocardial infarction in the thrombolytic era. A prospective trial.
Authors: Hohnloser S H , Franck P , Klingenheben T , Zabel M , Just H
Published: June 2012

BACKGROUND

Successful reperfusion of the infarct-related artery in patients with acute myocardial infarction has been shown to reduce in-hospital as well as 1-year mortality. Besides the thrombolysis-induced myocardial salvage, there is increasing evidence that an open infarct-related artery results in increased electrical stability of the heart and that this effect is at least in part responsible for the favorable long-term outcome of these patients. The exact incidence of arrhythmic events during the first year after myocardial infarction and the predictive value of different risk factors for these complications, however, have not been determined in patients in the thrombolytic era.

METHODS AND RESULTS

A total of 173 patients with acute myocardial infarction, 51% treated with thrombolysis, were prospectively entered into the study. At the time of hospital discharge, signal-averaged ECG, Holter monitoring, radionuclide angiography, coronary angiography, and levocardiography were performed in all patients. An open infarct-related artery was documented in 136 patients. The overall incidence of late potentials was 24% (41 patients). By multivariate analysis, an occluded infarct-related artery (P = .04) and the presence of regional wall motion abnormalities (P = .02) were the strongest independent predictors for the development of a late potential. Residual ischemia was treated by either percutaneous transluminal coronary angioplasty or surgery in 86 of 173 patients (50%). Seventy percent of the patients received beta-blocker therapy. During a mean follow-up of 12 +/- 5 months, 7 patients died suddenly or had ventricular fibrillation documented, while only 2 developed sustained monomorphic ventricular tachycardia. Overall 1-year mortality was 4.1%. Multivariate analysis revealed only an occluded infarct-related artery as an independent predictor of arrhythmic complications (P = .017).

CONCLUSIONS

In patients with acute myocardial infarction treated according to contemporary therapeutic guidelines, with a large proportion of individuals undergoing coronary artery revascularization, a low incidence of arrhythmic events, particularly of ventricular tachycardia, was observed in the first year after the index infarction. The presence or absence of an open infarct-related artery was the strongest independent predictor of these events, whereas other traditional risk factors, such as late potentials, were less helpful in identifying patients prone to sudden death. These findings emphasize the importance of the open artery hypothesis in patients recovering from acute myocardial infarction.
Prognostic implications of baseline electrocardiographic features and their serial changes in subjects with left ventricular hypertrophy.
Authors: Levy D , Salomon M , D'Agostino R B , Belanger A J , Kannel W B
Published: June 2012

BACKGROUND

During the past half-century, the ECG has been used extensively for the diagnosis of left ventricular hypertrophy. Persons with ECG evidence of left ventricular hypertrophy are at increased risk for the development of cardiovascular disease.

METHODS AND RESULTS

Subjects from the Framingham Heart Study with ECG evidence of left ventricular hypertrophy were eligible for this investigation if they were free of cardiovascular disease and did not have complete bundle-branch block or Wolff-Parkinson-White syndrome. Logistic regression analyses of pooled biennial examinations were used to determine risk for cardiovascular disease as a function of baseline voltage (sum of R wave in aVL plus S wave in V3) and repolarization and as a function of serial changes in these ECG features of hypertrophy. The eligible sample consisted of 274 men (mean age, 60 years) and 250 women (mean age, 64 years) who contributed 2660 person-examinations. During follow-up, there were 269 new cardiovascular events. Compared with subjects in the first quartile of voltage at baseline, the age-adjusted odds ratio for cardiovascular disease among subjects in the fourth quartile was 3.08 (95% confidence interval [CI], 1.87 to 5.07) in men and 3.29 (95% CI, 1.78 to 6.09) in women. Compared with a normal repolarization pattern, the presence of severe repolarization abnormalities was associated with an age-adjusted odds ratio of 5.84 (95% CI, 3.55 to 9.62) in men and 2.47 (95% CI, 1.38 to 4.42) in women. Subjects with a serial decline in voltage were at lower risk for cardiovascular disease than were those with no serial change (men: odds ratio after adjusting for age and baseline voltage, 0.46; 95% CI, 0.26 to 0.84; women: odds ratio, 0.56; 95% CI, 0.30 to 1.04). In contrast, those with a serial increase in voltage were at greater risk for cardiovascular disease (men: odds ratio, 1.86; 95% CI, 1.14 to 3.03; women: odds ratio, 1.61; 95% CI, 0.91 to 2.84). Compared with those with no serial change, an improvement in repolarization was associated with a marginally significant reduction in cardiovascular risk in men (odds ratio after adjusting for age and baseline repolarization, 0.45; 95% CI, 0.20 to 1.01). Worsening of repolarization was associated with increased risk for cardiovascular disease in both sexes (men: odds ratio, 1.89; 95% CI, 1.05 to 3.40; women: odds ratio, 2.02; 95% CI, 1.07 to 3.81).

CONCLUSIONS

The results of this investigation suggest that regression of ECG features of left ventricular hypertrophy confers an improvement in risk for cardiovascular disease, whereas serial worsening imposes increased risk. The benefits to be derived from regression of left ventricular hypertrophy must be confirmed in other clinical settings.
Arterial baroreflex control of renal hemodynamics in humans.
Authors: van Tilborg K A , Rabelink T J , van Rijn H J , Boomsma F , Koomans H A
Published: June 2012

BACKGROUND

Control of renal hemodynamics by the arterial baroreflex has never been proved in humans. Apart from the physiological viewpoint, this issue is relevant because altered baroreflex function has been implicated in the pathogenesis of human hypertension.

METHODS AND RESULTS

Renal function studies were performed in seated healthy volunteers (n = 12; age range, 20 to 34 years) during sustained neck suction at -60 mm Hg, aiming to selectively activate the carotid sinus arterial baroreceptors. Two protocols were followed. One group of 6 volunteers taking a 20 mmol/d sodium diet underwent 90 minutes of neck suction. Compared with a time-control study, neck suction decreased arterial pressure and heart rate; increased glomerular filtration rate (inulin clearance) from 104 +/- 6 to 114 +/- 8 mL/min (P < .01), renal plasma flow (para-aminohippurate clearance) from 616 +/- 52 to 665 +/- 42 mL/min (P < .01), and renal blood flow (from 1120 +/- 95 to 1209 +/- 77 mL/min, P < .01); and decreased renal vascular resistance (from 86 +/- 8 to 76 +/- 6 mm Hg.min.L-1, P < .01). Neck suction had no effect on plasma renin activity, aldosterone, atrial natriuretic peptide, catecholamines, and renal sodium excretion. The other 6 volunteers took a normal sodium diet and underwent sustained neck suction for 60 minutes. In this group, no effects on renal hemodynamics could be discerned, despite a modest decrease in blood pressure and heart rate.

CONCLUSIONS

These data show, for the first time, that the arterial baroreflex is involved in the control of renal hemodynamics in humans. However, basal arterial baroreflex control of renal hemodynamics is probably low, and arterial baroreflex activation with subsequent renal vasorelaxation may be found only in conditions in which basal arterial baroreflex control of kidney function is significant, as is presumably the case in seated sodium-restricted subjects.
Fibrin-targeted recombinant hirudin inhibits fibrin deposition on experimental clots more efficiently than recombinant hirudin.
Authors: Bode C , Hudelmayer M , Mehwald P , Bauer S , Freitag M , von Hodenberg E , Newell J B , Kübler W , Haber E , Runge M S
Published: June 2012

BACKGROUND

Although the indirect thrombin inhibitor heparin and the more potent direct inhibitor hirudin are useful in preventing thrombosis, a substantial opportunity remains for improving the thrombus selectivity of thrombin inhibitors.

METHODS AND RESULTS

To explore the effect of targeting an antithrombin to the surface of a clot, we covalently linked recombinant hirudin to the Fab' (or IgG) of a monoclonal antibody (59D8) that selectively binds to an epitope on fibrin that becomes exposed only after thrombin cleaves fibrinopeptide B. Antibody-coupled hirudin bound to an immobilized peptide of the fibrin beta-chain amino-terminal sequence and inhibited the peptidolytic activity of thrombin more efficiently than free hirudin. Thrombin inhibition dependent on binding to immobilized fibrin monomer was enhanced 1100-fold (P < .0001). Hirudin-59D8 Fab' was 10 times more effective than hirudin in inhibiting fibrin deposition on experimental clot surfaces in fibrinogen solution (P < .0001) and human plasma (P < .0001). The more effective inhibition of thrombin by the conjugate was supported by significantly diminished concentrations of fibrinopeptide A in the plasma supernatant of the clot (P = .0001). Inhibition of clotting by an uncoupled mixture of hirudin and 59D8 Fab' was indistinguishable from that by hirudin alone, indicating that the conjugate's greater inhibitory activity was due to the covalent linkage between antibody and hirudin.

CONCLUSIONS

Fibrin-targeted hirudin (in comparison with unmodified hirudin) significantly reduces fibrin deposition on the surface of experimental clots.
Nitric oxide accounts for dose-dependent estrogen-mediated coronary relaxation after acute estrogen withdrawal.
Authors: Collins P , Shay J , Jiang C , Moss J
Published: June 2012

BACKGROUND

Estrogen replacement therapy reduces the risk of coronary heart disease in postmenopausal women, and estrogen treatment modulates endothelium-dependent vasodilation in ovariectomized, atherosclerotic monkeys. Estradiol-17 beta also induces relaxation in isolated rabbit coronary arteries as well as cerebral basilar arteries. The estrogen concentrations required to induce such relaxation are in the pharmacological range (10(-6) to 10(-5) mol/L).

METHODS AND RESULTS

The present study was designed to test whether the sensitivity and specificity of the relaxing response of coronary vascular smooth muscle to exogenous estradiol-17 beta is dependent on the sex hormone status of the animal. In coronary artery rings contracted with PGF2 alpha (3 x 10(-5) mol/L), estradiol-17 beta caused significant relaxation at a physiological estrogen concentration (10(-9) mol/L), in coronary artery rings from oophorectomized, estrogen-treated and acutely estrogen-withdrawn rabbits only. Relaxation induced by estradiol-17 beta at lower concentrations (10(-9) to 10(-6) mol/L) in these rings was 20 +/- 6%, 42 +/- 8%, 54 +/- 9%, and 75 +/- 8%, respectively, compared with 4 +/- 2%, 12 +/- 5%, 16 +/- 7%, and 25 +/- 12% and 5 +/- 2%, 12 +/- 5%, 18 +/- 8%, and 23 +/- 10% in rings from estrogen-maintained and oophorectomized rabbits, respectively (P < .01). The relaxation in coronary artery rings from estrogen-treated and acutely estrogen-withdrawn rabbits was endothelium and nitric oxide dependent since it was abolished by endothelium removal and the nitric oxide synthase inhibitor N omega-nitro-L-arginine.

CONCLUSIONS

This study demonstrates that estrogen-induced, endothelium-dependent relaxation of coronary arteries may, in some species, depend on the sex hormone status of the animal. These findings may help to better understand the effects of ovarian steroids in the coronary circulation of females.
A polymorphism of the angiotensinogen gene associated with variation in blood pressure in a genetic isolate.
Authors: Hegele R A , Brunt J H , Connelly P W
Published: June 2012

BACKGROUND

The Hutterite Brethren are a genetic isolate characterized by high indices of relatedness and a communal agrarian lifestyle. We hypothesized that variation of the angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) genes would be associated with variation in resting blood pressure in this group. We also hypothesized that the association would depend on the sex of the subjects.

METHODS AND RESULTS

In 741 Hutterites, we measured blood pressure in quadruplicate and analyzed DNA for genotypes of an insertion/deletion (I/D) polymorphism of ACE and of two protein polymorphisms of AGT, namely, M235T and T174M. We tested for association between variation in systolic and diastolic blood pressures and genotypic class. We observed that genotypes of AGT codon 174 were significantly associated with variation in systolic blood pressure. We also tested for an interaction between the AGT genotype and sex. We observed that genotypes of AGT codon 174 were significantly associated with variation in systolic blood pressure only in men. The AGT codon 174 polymorphism accounted for 3.1% of the total variation in systolic blood pressure in men.

CONCLUSIONS

The association of AGT variation with resting blood pressure in men is consistent with the existence of important structural elements within, flanking, or proximal to the AGT gene, whose functional impact might be related to differences in sex.
Short stature and risk for mortality and cardiovascular disease events. The Framingham Heart Study.
Authors: Kannam J P , Levy D , Larson M , Wilson P W
Published: June 2012

BACKGROUND

Several studies have observed an inverse association between height and risk for coronary disease, but it is unclear whether other traditional coronary disease risk factors may have confounded this association. We examined the original Framingham Heart Study cohort to determine whether short stature is associated with all-cause mortality, cardiovascular disease mortality, and myocardial infarction after adjusting for age and other traditional coronary heart disease risk factors.

METHODS AND RESULTS

A total of 2019 men and 2585 women were followed up to 35.6 years. Subjects were stratified by sex and divided into quartiles according to height. Risk ratios were calculated from proportional hazards analyses comparing the first, second, and third quartiles of height to the tallest quartile before and after adjusting for age, hypertension, smoking, serum cholesterol, diabetes, relative weight, and alcohol intake. In both sexes, there were significant differences in the unadjusted event rates between the shortest and the tallest quartile for all-cause mortality, cardiovascular mortality, and myocardial infarction. Once the analyses were age adjusted, differences among height quartiles persisted only for risk of myocardial infarction in women. Further adjustment for other clinical variables had little additional impact on the results.

CONCLUSIONS

After considering age and other coronary disease risk factors, short stature was not associated with increased risk for all-cause or cardiovascular mortality in either sex. It was associated with increased risk for myocardial infarction in women but not in men.
Origin of both coronary arteries from the pulmonary artery.
Authors: Urcelay G E , Iannettoni M D , Ludomirsky A , Mosca R S , Cheatham J P , Danford D A , Bove E L
Published: June 2012

Origin of both coronary arteries from the pulmonary artery is generally a lethal condition from progressive ventricular failure. We report the clinical and surgical course of two infants, ages 3 and 6 months, with this anomaly. One patient had normal intracardiac anatomy with low pulmonary artery pressures (30/12 mm Hg). The second patient had a restrictive subpulmonic ventricular septal defect with a moderately elevated pulmonary artery pressure (50/13 mm Hg). Left ventricular ejection and shortening fractions were profoundly depressed in both patients. The common coronary trunk arose from the right anterior facing sinus in one patient and from the left posterior facing sinus in the other. Both patients underwent repair by direct coronary implantation to the aorta. Left ventricular function improved with shortening fractions near normal at a follow-up of 6 months for one patient and 1 year for the other. Early diagnosis and prompt repair is compatible with survival and return of normal shortening fraction.
Role of protein kinase C-mediated pathway in the pathogenesis of coronary artery spasm in a swine model.
Authors: Ito A , Shimokawa H , Nakaike R , Fukai T , Sakata M , Takayanagi T , Egashira K , Takeshita A
Published: June 2012

BACKGROUND

The intracellular mechanism of coronary artery spasm is still unknown. The pathway mediated by protein kinase C (PKC) is an important intracellular process of various cellular responses, including vascular smooth muscle contraction. Thus, we examined the role of the PKC-mediated pathway in the pathogenesis of coronary artery spasm in our in vivo swine model.

METHODS AND RESULTS

Seven Göttingen miniature pigs underwent coronary balloon injury and x-ray irradiation to induce atherosclerotic lesion. After 6 to 18 months, intracoronary serotonin (3 micrograms/kg) or histamine (3 micrograms/kg) repeatedly induced coronary artery spasm at the atherosclerotic site. At the spastic site, intracoronary administration of phorbol-12,13-dibutyrate (PDBu) (10(-9) mol/kg), a PKC-activating phorbol ester, also induced coronary artery spasm, which was completely blocked by pretreatment with intracoronary staurosporine (10 micrograms/kg), a PKC inhibitor. Intracoronary administration of an inactive phorbol ester, phorbol-12,13-didecanoate (10(-9) mol/kg), did not induce coronary vasoconstriction. Coronary artery spasm induced by the autacoids was significantly augmented by pretreatment with intracoronary PDBu and partially inhibited by staurosporine. Intracoronary administration of Bay K 8644 (10 micrograms/kg), a dihydropyridine-sensitive L-type calcium channel agonist, also induced coronary artery spasm at the spastic site, which was significantly inhibited by pretreatment with intracoronary staurosporine or nifedipine (0.1 mg/kg).

CONCLUSIONS

These results suggest (1) the PKC-mediated pathway is importantly involved in the pathogenesis of coronary artery spasm, (2) activation of the PKC-mediated pathway partially accounts for serotonin- and histamine-induced coronary artery spasm, and (3) at the spastic site, calcium influx through dihydropyridine-sensitive L-type calcium channel and/or calcium sensitivity of the contractile proteins may be augmented by the PKC-mediated pathway.
Right atrial and right ventricular transmural pressures in dogs and humans. Effects of the pericardium.
Authors: Hamilton D R , Dani R S , Semlacher R A , Smith E R , Kieser T M , Tyberg J V
Published: June 2012

BACKGROUND

To determine the transmural pressure-dimension relations of the right atrium (RA) and right ventricle (RV) before and after pericardiectomy, six open-chest dogs were instrumented with pericardial balloons placed over the RA and RV free walls.

METHODS AND RESULTS

PA appendage dimensions and RV free-wall segment lengths were measured using sonomicrometry. Intact-pericardium RA and RV transmural pressures were calculated by subtracting the pericardial pressures (measured using balloons) from the cavitary pressures. Pooled data from six animals with pericardium intact indicate that at RA and RV cavitary pressures of 5, 10, and 15 mm Hg, RV pericardial pressure was 4.3 +/- 0.3, 8.6 +/- 1.0, and 13.3 +/- 1.5 mm Hg, respectively, and RA pericardial pressure was 4.8 +/- 0.3, 9.6 +/- 0.6, and 14.6 +/- 0.6 mm Hg, respectively (mean +/- SD). With calculated unstressed dimensions, the cavity dimension data were normalized to strain (in percent). We determined that in the dog, RV strain would increase by 14% and RA by 68% to maintain cavitary pressure at 10 mm Hg on pericardiectomy. To compare these results with clinical data, RV (n = 7) and RA (n = 6) transmural pressures were measured using balloons in patients (age, 19 to 76 years) undergoing cardiac surgery. RA transmural pressure of six patients was 1.0 +/- 1.5 mm Hg when central venous pressures (CVPs) ranged from 3 to 16 mm Hg. RV transmural pressure equaled 1.2 +/- 1.9, 2.3 +/- 1.9, and 3.4 +/- 2.0 mm Hg when CVP was 5, 10, and 15 mm Hg, respectively.

CONCLUSIONS

Pericardial constraint (as evaluated by the ratio of pericardial to intracavitary pressures when CVP is 10 mm Hg) accounted for 96% of RA cavitary pressure in the dog and 89% in humans and at least 86% of RV cavitary pressure in the dog and 77% in humans.
Radiofrequency ablation of slow pathway in patients with atrioventricular nodal reentrant tachycardia. Do arrhythmia recurrences correlate with persistent slow pathway conduction or site of successful ablation?
Authors: Manolis A S , Wang P J , Estes N A
Published: June 2012

BACKGROUND

Residual slow pathway conduction in the form of persistent jump in the atrioventricular (AV) conduction time or atrial echo beats is a common finding after successful radiofrequency (RF) ablation of the slow pathway in patients with AV nodal reentrant tachycardia (AVNRT). Sites of successful RF ablation of the slow pathway may be located anteriorly in the tricuspid annulus (cephalad to the coronary sinus os) or posteriorly (at, within, or caudal to the coronary sinus os). The aim of this study was to investigate whether arrhythmia recurrences correlate with persistent slow pathway conduction or site of successful ablation.

METHODS AND RESULTS

Among 55 patients with symptomatic AVNRT having RF ablation, 23 patients (42%) (group 1) had evidence of persistent dual AV nodal pathway physiology and/or echo beats, whereas in 32 patients (group 2), slow pathway conduction had been completely eliminated. With regard to ablation sites, 14 patients (25%) (group A) had their slow pathway successfully ablated at an inferoposterior site, whereas in 41 patients (group B), the ablation site was located anteriorly to the coronary sinus os. The study patients included 17 men and 38 women, aged 37 +/- 18 years. The electrophysiological study and RF ablation were performed in a single session in 50 patients (91%). After the first session, the technique was successful in all patients (100%), with elimination of AVNRT and without affecting AV conduction. A mean of 9 +/- 6 lesions were applied. The total procedure time averaged 4 +/- 1 hours. Fluoroscopy time was 41 +/- 25 minutes. Except for transient AV block in 1 patient, no other complications occurred. Over 12 +/- 8 months, a total of 7 patients (13%) had recurrence of AVNRT, and 6 of them underwent successful repeat slow pathway RF ablation. Recurrence rate was 9% (2 patients) for group 1, with persistent jump or echo beats, and 16% (5 patients) for group 2, without residual slow pathway conduction (P = NS). Five of the recurrences (71%) were noted in group A and 2 in group B. Thus, the recurrence rate was 36% for group A (5 of 14 patients), with posterior ablations, and 5% for group B (2 of 41 patients), with anterior sites of successful RF ablation (P < .05).

CONCLUSIONS

After successful RF ablation of the slow pathway in patients with AVNRT, residual slow pathway conduction does not correlate with clinical tachycardia recurrences. However, the site of successful RF ablation of the slow pathway does correlate with arrhythmia recurrences. More recurrences are observed when the site is located inferoposteriorly, at or below the os of the coronary sinus, as compared with medial and anterior locations of the ablation site.
Relation of Ultrasonic Backscatter and Acoustic Propagation Properties to Myofibrillar Length and Myocardial Thickness
Authors: O’Brien Patrick D. , O’Brien William D. , Rhyne Theodore L. , Warltier David C. , Sagar Kiran B.
Published: June 2012

Background
Ultrasonic backscatter demonstrates a cardiac cycle–dependent modulation. The exact mechanism of the modulation is under debate. The objective of the present study was to test the hypothesis that a change in size and configuration of myofilaments from systole to diastole alters acoustic propagation properties and backscatter.

Methods and Results
In vivo measurements were made of integrated backscatter at 5 MHz (IBR5), followed by in vitro measurements of ultrasonic attenuation, speed, and heterogeneity index using a scanning laser acoustic microscope at 100 MHz. Studies were performed in canine hearts (16) arrested in systole (8) with calcium chloride or arrested in diastole (8) with potassium chloride. Sarcomere length was measured with a calibrated eyepiece on a Ziess microscope. Wall thickness was measured with calipers. The attenuation coefficient of 220±34 dB/cm during systole was significantly higher than the coefficient of 189±24 dB/cm during diastole (
P
<.01); the IBR5 of −44.7±1.2 dB during systole was significantly greater than the IBR5 of −47.0±1.0 dB during diastole (
P
<.01); the ultrasonic speed of 1591±11 m/s during systole was higher than the speed of 1575±4.2 m/s during diastole (
P
<.01); and the heterogeneity index of 7.4±1.8 m/s during systole was significantly lower than the index of 9.0±2.0 m/s during diastole (
P
<.02). The sarcomere length of 1.804±0.142 μm during diastole was significantly higher than the length of 1.075±0.177 μm during systole (
P
<.01). Wall thickness was significantly greater during systole than during diastole (20±3 versus 9±3 mm,
P
<.01).

Conclusions
Ultrasonic backscatter and propagation properties are directly related to sarcomere length and myocardial thickness and may be responsible for cardiac cycle–dependent variation in backscatter.
Sudden Death, Impaired Glucose Tolerance, and Diabetes in Japanese American Men
Authors: Curb J. David , Rodriguez Beatriz L. , Burchfiel Cecil M. , Abbott Robert D. , Chiu Darryl , Yano Katsuhiko
Published: June 2012

Background
Diabetes and glucose intolerance have been shown to increase the risk of cardiovascular mortality in a number of different populations. Most studies have been based on short follow-up periods, and few have had sufficient numbers to allow researchers to look at sudden death as an outcome.

Methods and Results
The relation of sudden death, defined as unexpected death occurring within either 1 or 24 hours of first symptoms, to glucose intolerance measured by a nonfasting 1-hour postload measurement made in 1965 or history of diabetes was examined by use of 23 years of follow-up on the 8006 participants enrolled in the Honolulu Heart Program. After adjustment for baseline body mass index, hypertension, cholesterol, triglycerides, smoking, alcohol consumption, and left ventricular hypertrophy or strain, the relative risks for sudden death within 24 hours in individuals with high-normal (151 to 224 mg/dL), asymptomatic high glucose values (≥225 mg/dL), and diabetes compared with those with lower glucose values (<151 mg/dL) were 1.59, 2.22, and 2.76, respectively. All these relative risks were statistically significant (
P
≤.05). Trends for sudden death in 1 hour were similar. Among men with sudden death <1 hour after onset of symptoms, the strength of the association between diabetes and sudden death was stronger among those classified as having died of unknown causes who thus were more likely to have died of an arrhythmia than among those classified as having died of coronary heart disease.

Conclusions
The relations seen in these analyses indicate that individuals with glucose intolerance or diagnosed diabetes are at increased risk for sudden death.