bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise-Induced Coronary Artery Vasodilation Is Not Impaired by Stent Placement
Authors: Maier Willibald , Windecker Stephan , Küng Adrian , Lütolf Roland , Eberli Franz R. , Meier Bernhard , Hess Otto M.
Published: July 2002

Background

—

Stenting has proved beneficial for treating threatened closure and reducing restenosis after balloon angioplasty. However, the implantation of a coronary metallic prosthesis has been related to impaired vasomotion distal to the stent as assessed by acetylcholine infusion. Thus, the purpose of the present study was to determine the vasomotion of stented coronary arteries and to assess its influence on the vasomotion of adjacent vessel segments during bicycle exercise.

Methods and Results

—

Biplane quantitative coronary angiography was performed at rest and during bicycle exercise in 26 patients with coronary artery disease. Twelve patients had single vessel disease with stable angina pectoris (controls; group 1). Fourteen patients underwent coronary stenting for therapeutic reasons and were studied 10±3 months after the intervention (group 2). Minimal luminal area, stent area, and proximal and distal vessel areas were determined. In controls (group 1), vasoconstriction of the stenotic artery (− 29±4%;
P
<0.001) was observed during exercise, whereas the normal segment showed vasodilation (15±4%;
P
<0.05). In group 2, vasomotion of the stented segment was eliminated (0±1%), whereas the proximal and distal segments showed exercise-induced vasodilation (8±2% and 11±3%, respectively;
P
<0.005), which was not different from control segments (10±2%). Sublingual nitroglycerin was associated with maximal vasodilation of the proximal and distal vessel segments (30±8% and 38±13%, respectively;
P
<0.005).

Conclusions

—

In contrast to the vasoconstriction of vessels in control patients, normal vasodilation of proximal and distal segments occurred during the physiological stress of exercise in patients with coronary stent placement. As expected, vasomotion was abolished in the stented region.
Initial Clinical Experience With the Jarvik 2000 Implantable Axial-Flow Left Ventricular Assist System
Authors: Frazier O. H. , Myers Timothy J. , Gregoric Igor D. , Khan Tehreen , Delgado Reynolds , Croitoru Mihai , Miller Kathy , Jarvik Robert , Westaby Stephen
Published: July 2002

Background
—

Implantable left ventricular assist systems (LVASs) are used for bridging to transplantation, bridging to myocardial improvement, and for permanent circulatory support. Conventional implantable systems have inherent limitations that increase morbidity during support. In contrast, small, efficient, axial-flow pumps, which have been under development for the past decade, have the potential to improve the length and quality of life in patients with severe heart failure.

Methods and Results
—

To assess the safety and clinical utility of the Jarvik 2000, we implanted this device in 10 transplant candidates (mean age 51.3 years) in New York Heart Association (NYHA) class IV. Implantation was achieved through a left thoracotomy during partial cardiopulmonary bypass. The mean support period was 84 days. Within 48 hours postoperatively, the cardiac index increased 43%, pulmonary capillary wedge pressure decreased 52%, systemic vascular resistance decreased significantly, and inotropic support became unnecessary. Eight patients underwent physical rehabilitation and returned to NYHA class I. Their left ventricular dimensions, cardiothoracic ratios, and pressure-volume loop analyses showed good left ventricular unloading. Seven patients underwent transplantation and 3 died during support. No device thrombosis was observed at explantation.

Conclusions
—

The Jarvik 2000 functions as a true assist device by partially unloading the left ventricle, thereby optimizing the patient’s hemodynamics. Our preliminary results indicate that this LVAS may safely provide circulatory assistance for heart transplant candidates.
Influence of C3 Deficiency on Atherosclerosis
Authors: Buono Chiara , Come Carolyn E. , Witztum Joseph L. , Maguire Graham F. , Connelly Philip W. , Carroll Michael , Lichtman Andrew H.
Published: July 2002

Background

—

The influence of complement activation on atherosclerosis is not well understood. The purpose of this study was to examine the effects of C3 deficiency on the extent and phenotype of atherosclerosis.

Methods and Results

—

Aortic atherosclerosis was analyzed in low-density lipoprotein receptor (ldlr)/C3-deficient mice (
ldlr
−/−
C3
−/−
) and
ldlr
−/−
C3
+/−
littermate control mice after 15 weeks on a 1.25% (wt/wt) cholesterol diet. Serum lipoprotein profiles and immunoglobulin levels were not significantly different between the 2 experimental groups. The lipid-positive en face lesional area in thoracic and abdominal aorta was greater in C3-deficient mice than in control mice (3.9% versus 2.1%, median,
P
=0.0076). Similarly
,
the lipid-positive area in aortic arch sections was greater in C3-deficient mice than in controls (0.04 mm
2
versus 0.02 mm
2
, median,
P
=0.0089). Analysis of aortic arch sections showed greater lesional macrophage content in C3-deficient versus control mice (8.24±1.36% versus 5.9±1.63% intimal area, mean±SEM,
P
=0.003), less smooth muscle cell content in C3-deficient versus control mice (0.06±0.05% versus 0.92±0.32% intimal area, mean±SEM,
P
<0.0001), and less collagen content in C3-deficient versus control mice (0.52±1.26% versus 11±10.43% intimal area, mean±SEM,
P
=0.008).

Conclusions

—

The maturation of atherosclerotic lesions beyond the foam cell stage is strongly dependent on an intact complement system.
Prevention of Accelerated Atherosclerosis by Angiotensin-Converting Enzyme Inhibition in Diabetic Apolipoprotein E–Deficient Mice
Authors: Candido Riccardo , Jandeleit-Dahm Karin A. , Cao Zemin , Nesteroff Stefan P. , Burns Wendy C. , Twigg Stephen M. , Dilley Rodney J. , Cooper Mark E. , Allen Terri J.
Published: July 2002

Background

—

Atherosclerosis is a major complication of diabetes, but the mechanisms by which diabetes promotes macrovascular disease have not been fully delineated. Although several animal studies have demonstrated that inhibition of ACE results in a decrease in the development of atherosclerotic lesions, information about the potential benefits of these agents on complex and advanced atherosclerotic lesions as observed in long-term diabetes is lacking. The aim of this study was to evaluate whether treatment with the ACE inhibitor perindopril affects diabetes-induced plaque formation in the apolipoprotein E (apoE)-deficient mouse.

Methods and Results

—

Diabetes was induced by injection of streptozotocin in 6-week-old apoE-deficient mice. Diabetic animals received treatment with perindopril (4 mg · kg
−1
· d
−1
) or no treatment for 20 weeks. Nondiabetic apoE-deficient mice were used as controls. Induction of diabetes was associated with a 4-fold increase in plaque area compared with nondiabetic animals. This accelerated atherosclerosis was associated with a significant increase in aortic ACE expression and activity and connective tissue growth factor and vascular cell adhesion molecule-1 expression. Perindopril treatment inhibited the development of atherosclerotic lesions and diabetes-induced ACE, connective tissue growth factor, and vascular cell adhesion molecule-1 overexpression in the aorta.

Conclusions

—

The activation of the local renin-angiotensin system in the diabetic aorta and the reduction in atherosclerosis with ACE inhibitor treatment provides further evidence that the renin-angiotensin system plays a pivotal role in the development and acceleration of atherosclerosis in diabetes.
Probucol Attenuates Left Ventricular Dysfunction and Remodeling in Tachycardia-Induced Heart Failure
Authors: Nakamura Ryo , Egashira Kensuke , Machida Youji , Hayashidani Shunji , Takeya Motohiro , Utsumi Hideo , Tsutsui Hiroyuki , Takeshita Akira
Published: July 2002

Background

—

Oxidative stress and inflammation are potentially involved in the pathogenesis of heart failure (HF). We examined whether antioxidant and antiinflammatory treatment with probucol decreases myocardial oxidative stress and inflammation and attenuates the progression of left ventricular (LV) dysfunction and remodeling (dilatation) in tachycardia-induced HF.

Methods and Results

—

We studied 3 groups of dogs: a sham-operated control group and 2 other groups that underwent ventricular pacing at 240 bpm with and without probucol treatment (100 mg/kg IP per week) for 4 weeks. Dogs that underwent ventricular pacing for 4 weeks developed signs of HF, such as a reduction in the LV ejection fraction and increases in the LV end-diastolic dimension and LV end-diastolic pressure. Myocardial oxidative stress, as measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6,-tetramethyl-piperidine-
N
-oxyl (hydroxy-TEMPO), was significantly increased. There was an increase in myocardial monocyte infiltration, monocyte chemoattractant protein-1 expression, and renin-angiotensin system and matrix metalloproteinase activity. Probucol treatment prevented increases in oxidative stress, inflammation, and matrix metalloproteinase activity and attenuated LV dysfunction and remodeling.

Conclusions

—

Probucol attenuated LV dysfunction and remodeling, possibly through its antioxidant and/or antiinflammatory effects in ventricular pacing–induced HF. These data suggest that inflammatory disorders, which cause an abnormal interaction between failing myocardium and activated monocytes, have an important role in the progression of HF.
Chemical Mediators of the Muscle Ergoreflex in Chronic Heart Failure
Authors: Scott Adam C. , Wensel Roland , Davos Constantinos H. , Kemp Michael , Kaczmarek Agnieszka , Hooper James , Coats Andrew J.S. , Piepoli Massimo F.
Published: July 2002

Background

—

The overactivity of ergoreceptors (intramuscular afferents sensitive to products of skeletal muscle work) may be responsible for the abnormal responses to exercise and symptoms of exercise intolerance in chronic heart failure (CHF); however, little is known of the chemical nature of the stimuli involved. We investigated biochemical factors (H
+
, V̇
co
2
, V̇
o
2
, H
co
3
, K
+
, phosphate, lactate, PGE
2
, PGF
1α
, and bradykinin) potentially involved in ergoreceptor activation.

Methods and Results

—

Sixteen stable patients with CHF (64.9±2.7 years, peak V̇
o
2
15.8±0.7 mL/kg per min) and 10 age-matched controls were studied. The ergoreceptor test involved two 5-minute handgrip exercises. On one occasion, the subjects recovered normally (control recovery), whereas on the other a posthandgrip regional circulatory occlusion was induced in the exercising arm, isolating the stimulation of the ergoreceptor after exercise. The ergoreflex was quantified as the difference in ventilation between the posthandgrip regional circulatory occlusion and the control recovery periods. During the protocol, the local muscular blood effluent concentrations of metabolic mediators were assessed. Patients had an ergoreflex effect on ventilation greater than controls (4.8±1.4 versus 0.4±0.1 L/min,
P
<0.01). During the ergoreflex test in patients, the following metabolites were elevated with respect to resting values in comparison with controls: PGE
2
(3.7±0.7 versus 1.1±0.2 pg/mL), PGF
1α
(16.2±2.8 versus 7.2±1.2 pg/mL), and bradykinin (2.1±0.3 versus 1.0±0.1 pg/mL),
P
<0.05 for all comparisons. Only the increases in prostaglandins were predictors of the ergoreflex response (
r
>0.41,
P
<0.01).

Conclusions

—

Although multiple metabolites are concentrated in exercising muscle in CHF, only prostaglandins correlated with ergoreflex activity, suggesting these factors as potential triggers to the exaggerated ergoreflex, which is characteristic of CHF. This may have important implications for novel therapies to improve exercise tolerance.
Activation of Protein Kinases in Chronically Hypoxic Infant Human and Rabbit Hearts
Authors: Rafiee Parvaneh , Shi Yang , Kong Xiangrong , Pritchard Kirkwood A. , Tweddell James S. , Litwin S. Bert , Mussatto Kathleen , Jaquiss Robert D. , Su Jidong , Baker John E.
Published: July 2002

Background

—

Many infants who undergo heart surgery have a congenital cyanotic defect in which the heart is chronically perfused with hypoxic blood. However, the signaling pathways by which infant hearts adapt to chronic hypoxia and resist subsequent surgical ischemia is unknown.

Method and Results

—

We determined the activation and translocation of protein kinase C (PKC) isoforms and mitogen activated protein kinases (MAP kinases) in 15 infants with cyanotic (Sa
o
2
<85%) or acyanotic (Sa
o
2
>95%) heart defects undergoing surgical repair and in 80 rabbits raised from birth in a hypoxic (Sa
o
2
<85%) or normoxic (Sa
o
2
>95%) environment. Tissues from infant human and rabbit hearts were processed for Western and in vitro kinase analysis. In human infants with cyanotic heart defects, PKCε, p38 MAP kinase, and JUN kinase but not p42/44 MAP kinase were activated and translocated from the cytosolic to the particulate fraction compared with acyanotic heart defects. In rabbit infants there was a parallel response for PKCε, p38 MAP kinase, and JUN kinase similar to humans. In infant rabbit hearts inhibition of PKCε with chelerythrine, p38 MAP kinase, with SB203580 and JUN kinase with curcumin abolished the cardioprotective effects of chronic hypoxia but had no effects on normoxic hearts.

Conclusions

—

Infant human and rabbit hearts adapt to chronic hypoxia through activation of PKCε, p38 MAP kinase, and JUN kinase signal transduction pathways. These pathways may be responsible for cardioprotection in the chronically hypoxic infant rabbit heart.
Allopurinol Improves Endothelial Dysfunction in Chronic Heart Failure
Authors: Farquharson Colin A.J. , Butler Robert , Hill Alexander , Belch Jill J.F. , Struthers Allan D.
Published: July 2002

Background

—

Increased oxidative stress in chronic heart failure is thought to contribute to endothelial dysfunction. Xanthine oxidase produces oxidative stress and therefore we examined whether allopurinol improved endothelial dysfunction in chronic heart failure.

Methods and Results

—

We performed a randomized, placebo-controlled, double-blind crossover study on 11 patients with New York Heart Association class II-III chronic heart failure, comparing 300 mg allopurinol daily (1 month) versus placebo. Endothelial function was assessed by standard forearm venous occlusion plethysmography with acetylcholine, nitroprusside, and verapamil. Plasma malondialdehyde levels were also compared to assess significant changes in oxidative stress. Allopurinol significantly increased the forearm blood flow response to acetylcholine (percentage change in forearm blood flow [mean±SEM]: 181±19% versus 120±22% allopurinol versus placebo;
P
=0.003). There were no significant differences in the forearm blood flow changes between the placebo and allopurinol treatment arms with regard to sodium nitroprusside or verapamil. Plasma malondialdehyde was significantly reduced with allopurinol treatment (346±128 nmol/L versus 461±101 nmol/L, allopurinol versus placebo;
P
=0.03), consistent with reduced oxidative stress with allopurinol therapy.

Conclusions

—

We have shown that allopurinol improves endothelial dysfunction in chronic heart failure. This raises the distinct possibility that allopurinol might reduce cardiovascular events and even improve exercise capacity in chronic heart failure.
Cardiomyocytes of Noncardiac Origin in Myocardial Biopsies of Human Transplanted Hearts
Authors: Müller Patrick , Pfeiffer Peter , Koglin Jörg , Schäfers Hans-Joachim , Seeland Ute , Janzen Ingrid , Urbschat Steffi , Böhm Michael
Published: July 2002

Background

—

Cell replacement therapy with stem cells able to differentiate into cardiomyocytes has been discussed as a method for remodeling damaged myocardium. A physiological or pathophysiological situation in which this phenomenon might be relevant is not known. We studied the origin of cardiomyocytes in myocardial biopsies of male patients that had undergone sex-mismatched cardiac transplantation to determine whether cells containing a Y chromosome (and therefore being of recipient origin) are able to differentiate into cardiomyocytes.

Methods and Results

—

Myocardial biopsies (n=21) were obtained from the right ventricles of male patients (n=13) who had undergone sex-mismatched heart transplantation. Tissue from 1 nontransplanted male and myocardial biopsies from sex-matched heart–transplanted patients served as controls. Cells from donor and recipient origins were identified by fluorescence in situ hybridization with the use of specific probes for X and Y chromosomes on paraffin sections of the biopsies. Cell types were identified by using immunostaining procedures on the same tissue sections. Cardiomyocytes of recipient origin were detected in 8 of 13 male recipients of female hearts. They were connected by gap junctions with adjacent myocytes. Of the cardiomyocyte nuclei, 0.16±0.04% (mean±SEM, median 0.09%) contained the Y-chromosomal marker. There was no detectable correlation with the extent or number of rejection episodes, time of transplantation, or medical treatment regimen.

Conclusions

—

These results show that regeneration by cells of noncardiac origin (differentiated into cardiomyocytes and physiologically linked to neighboring myocytes) can be detected even in small myocardial biopsies. This may lead to new diagnostic and therapeutic strategies in the treatment of myocardial infarction, inflammatory heart disease, and/or heart failure.
Early Resolution of ST-Segment Elevation Correlates With Myocardial Salvage Assessed by Tc-99m Sestamibi Scintigraphy in Patients With Acute Myocardial Infarction After Mechanical or Thrombolytic Reperfusion Therapy
Authors: Dong Jun , Ndrepepa Gjin , Schmitt Claus , Mehilli Julinda , Schmieder Sebastian , Schwaiger Markus , Schömig Albert , Kastrati Adnan
Published: July 2002

Background

—

Early resolution of ST-segment elevation is an indicator of final infarct size and clinical outcomes. Whether this correlation is an expression of initial infarct characteristics or degree of myocardial salvage achieved with reperfusion therapy is unclear.

Methods and Results

—

We prospectively included 243 patients with acute myocardial infarction (AMI) treated with either coronary stenting (122 patients) or thrombolysis (121 patients). Serial 12-lead electrocardiograms (ECG) were performed at baseline and 90 minutes after initiation of therapy. ST-segment resolution was defined as complete (≥70%), partial (<70% to 30%), or no resolution (<30%). Paired technetium-99m sestamibi scintigraphic studies were performed to calculate the initial perfusion defect, final infarct size, and the proportion of initial defect salvaged with reperfusion (salvage index). ST-segment resolution correlated significantly with salvage index (
P
=0.008), final infarct size (
P
<0.001), and 6-month mortality (
P
=0.03). In the groups with complete, partial, and no resolution, salvage index was 0.54±0.32, 0.39±0.36, and 0.33±0.60; final infarct size was 12.5±12.0%, 20.0±13.9%, and 22.7±19.4% of the left ventricle; 6-month mortality was 2.4%, 6.2%, and 12.8%, respectively. After adjustment for baseline characteristics, ST-segment resolution was the second strongest predictor of salvage index (
P
=0.007) after the type of reperfusion, stenting, or thrombolysis (
P
=0.001); it was greater after stenting than after thrombolysis (
P
<0.001).

Conclusion

—

Early resolution of ST-segment elevation in surface ECG correlates with myocardial salvage as assessed by scintigraphy in patients with AMI after reperfusion therapy. These data provide an explanation for the favorable prognostic value of the ST-segment resolution and support the use of this parameter to compare the efficacy of different reperfusion strategies.
Evidence for Heritability of Abdominal Aortic Calcific Deposits in the Framingham Heart Study
Authors: O’Donnell Christopher J. , Chazaro Irmarie , Wilson Peter W.F. , Fox Caroline , Hannan Marian T. , Kiel Douglas P. , Cupples L. Adrienne
Published: July 2002

Background

—

Atherosclerosis is a systemic disease that underlies clinical cardiovascular disease. The radiographic finding of abdominal aortic calcific deposits is an indicator of the presence of aortic atherosclerosis and an independent predictor of cardiovascular disease events. Little is known about the heritability of aortic calcification.

Methods and Results

—

Original Framingham Heart Study cohort participants (2151) in 1109 extended pedigrees had a lateral lumbar radiograph. The presence and severity of abdominal aortic calcific (AAC) deposits at the levels of the first through fourth lumbar vertebrae was graded by a previously validated rating scale. Correlation coefficients were calculated in pairs of siblings, parent-offspring, and spouses. Age-, sex-, and multivariable-adjusted correlation coefficients for AAC were 0.52 for parent-offspring pairs and 0.20 for sibling pairs. In contrast, the multivariable-adjusted correlation for AAC in spouse pairs was −0.02. Using variance component methods implemented in SOLAR, the estimated heritability for age-, sex-, and multivariable-adjusted AAC was 0.49 (
P
<0.001). Thirty-one percent of the overall variance in AAC deposits was due to measured covariates, and 49% to heritable factors.

Conclusions

—

In our large, population-based sample, heritable factors play a role in the presence and extent of abdominal aortic calcification. Thus, a substantial proportion of the variation in AAC is due to additive effects of genes, which have yet to be characterized. Measures of aortic atherosclerosis may provide heritable quantitative phenotypes for the genetic dissection of the complex condition of atherosclerosis in human populations.
β
2
-Adrenergic Receptor Gene Delivery to the Endothelium Corrects Impaired Adrenergic Vasorelaxation in Hypertension
Authors: Iaccarino Guido , Cipolletta Ersilia , Fiorillo Antonia , Annecchiarico Mario , Ciccarelli Michele , Cimini Vincenzo , Koch Walter J. , Trimarco Bruno
Published: July 2002

Background

—

Impaired β-adrenergic receptor (AR)–mediated vasorelaxation in hypertension plays a role in increased peripheral vascular resistance and blood pressure. Because the β
2
AR is the most abundant vascular AR subtype, we sought to enhance βAR vasorelaxation by overexpressing β
2
ARs via adenoviral-mediated gene transfer (ADβ
2
AR) to the vascular endothelium of the carotid artery.

Methods and Results

—

In normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, we exposed the right common carotid artery to ADβ
2
AR in situ for 15 minutes by injection into the lumen while the blood flow was interrupted. Control carotids received an empty vector (ADempty). Three days later, transgene expression and selective endothelial localization were confirmed in infected vessels. Vasoregulation after β
2
AR overexpression (2-fold) was studied in isolated organ baths. ADβ
2
AR carotid responses to α
1
AR and α
2
AR agonists were not affected, whereas responses to epinephrine were altered and βAR-mediated vasorelaxation was enhanced after β
2
AR overexpression. As expected, βAR-mediated vasodilatation in control carotids of SHR rats was significantly less than in similar control WKY carotid arteries. ADβ
2
AR treatment enhanced βAR vasorelaxation in SHR to levels similar to those seen in ADβ
2
AR WKY carotids.

Conclusions

—

Our results demonstrate a critical role for the endothelium in βAR-mediated vasorelaxation and suggest that impaired βAR signaling may account for dysfunctional βAR vasorelaxation in hypertension rather than impaired endothelium-dependent nitric oxide metabolism.
Shortened Outflow Tract Leads to Altered Cardiac Looping After Neural Crest Ablation
Authors: Yelbuz T. Mesud , Waldo Karen L. , Kumiski Donna H. , Stadt Harriett A. , Wolfe Raymond R. , Leatherbury Linda , Kirby Margaret L.
Published: July 2002

Background

—

Congenital conotruncal malformations frequently involve dextroposed aorta. The pathogenesis of dextroposed aorta is not known but is thought to be due to abnormal looping and/or wedging of the outflow tract during early heart development. We examined the stage of cardiac looping in an experimental model of dextroposed aorta to determine the embryogenesis of this conotruncal malformation.

Methods and Results

—

Hearts were examined from neural crest–ablated embryos by using videocinephotography, scanning electron microscopy, and histological sections. The inflow and outflow limbs of the looped cardiac tube were malpositioned with respect to each other, the inner curvature was diminished, and the outflow limb was straighter and displaced cranially in a manner consistent with diminished length. The altered length could be explained by a significant reduction in the number of cells added to the myocardium of the distal outflow tract from the secondary heart field.

Conclusions

—

The data are consistent with research showing that normal looping and wedging are essential for normal alignment of the aorta with the left ventricle. These processes are abnormal in neural crest–ablated embryos because of a failure of the outflow tract to lengthen by the addition of myocardial cells from the secondary heart field.
Ambulatory Blood Pressure and Left Ventricular Mass Index in Hypertensive Children
Authors: Sorof Jonathan M. , Cardwell Gina , Franco Kathy , Portman Ronald J.
Published: July 2002

To determine whether ambulatory blood pressure is more predictive of left ventricular hypertrophy than is casual blood pressure in hypertensive children, echocardiography and ambulatory blood pressure data from 37 untreated hypertensive children were analyzed. Left ventricular mass was calculated using the Devereux equation, left ventricular mass index was calculated as left ventricular mass (in grams)/height
2.7
(in meters), and left ventricular hypertrophy was defined as left ventricular mass index >51 g/m
2.7
. Average blood pressure, blood pressure load, and blood pressure index (average blood pressure divided by pediatric ambulatory blood pressure 95th percentile) were calculated. Left ventricular mass index was strongly correlated with 24-hour systolic blood pressure index (
r
=0.43,
P
=0.008) and was also correlated with 24-hour systolic blood pressure (
r
=0.34,
P
=0.037), 24-hour systolic blood pressure load (
r
=0.38,
P
=0.020), wake systolic blood pressure load (
r
=0.37,
P
=0.025), sleep systolic blood pressure (
r
=0.33,
P
=0.048), and sleep systolic blood pressure load (
r
=0.38,
P
=0.021). Left ventricular mass index did not correlate with age, weight, clinic blood pressure, or ambulatory diastolic blood pressure. The overall prevalence of left ventricular hypertrophy was 27%. The prevalence of left ventricular hypertrophy was 47% (8 of 17) in patients with both systolic blood pressure load >50% and 24-hour systolic blood pressure index >1.0, compared with 10% (2 of 20) in patients without both criteria (
P
=0.015). These data suggest ambulatory blood pressure monitoring may be useful for the clinical assessment of hypertensive children by identifying those at high risk for the presence of end organ injury.
Diagnostic Value of the Post-Captopril Test in Primary Aldosteronism
Authors: Castro Oscar L. , Yu Xichun , Kem David C.
Published: July 2002

Primary aldosteronism is a disorder with hypertension, hypokalemia, increased plasma aldosterone, and suppressed renin activity. A random plasma aldosterone/renin activity (PA/PRA) >65 (conventional units ratio [CUR] >30) has been proposed as a screening test. We have retrospectively determined the value of the post-captopril plasma aldosterone/renin activity (CAPT PA/PRA) test for the diagnosis of patients with primary aldosteronism whose PA/PRA was <65. We considered the CAPT PA/PRA test to be positive for primary aldosteronism if either the plasma aldosterone concentration did not drop below 0.33 nmol/L (12 ng/dL) or the ratio was >26 (CUR >12). We found 6 patients with a random PA/PRA of 21 to 60 (CUR 10 to 28), yet with an abnormal post-captopril test criteria for primary aldosteronism. Five had an abnormal saline suppression test, and all 6 were confirmed by a combination of diagnostic localization with computerized axial tomography, iodocholesterol scan, adrenal venous sampling, and/or surgery. Four had idiopathic adrenal hyperplasia, and 2 had an aldosterone-producing adenoma. One other patient had an abnormal random plasma aldosterone/renin activity ratio of 99 (CUR 46), a negative saline infusion study, and was determined to have essential hypertension. In summary, the CAPT PA/PRA, but not the random PA/PRA, correctly diagnosed 6 patients with primary aldosteronism in our institution. An additional patient with essential hypertension was incorrectly diagnosed as having primary aldosteronism by the PA/PRA test. We conclude that the simple addition of 25 mg of captopril, taken orally 2 hours before sampling, enhances the accuracy for diagnosing patients with primary aldosteronism.
Effects of Dietary Sodium and Genetic Background on Angiotensinogen and Renin in Mouse
Authors: Lantelme Pierre , Rohrwasser Andreas , Gociman Barbu , Hillas Elaine , Cheng Tong , Petty Gray , Thomas Jennifer , Xiao Sha , Ishigami Tomoaki , Herrmann Tracy , Terreros Daniel A. , Ward Kenneth , Lalouel Jean-Marc
Published: July 2002

Elements of a renin-angiotensin system expressed along the entire nephron, including angiotensinogen secreted by proximal tubule and renin expressed in connecting tubule, may participate in the regulation of sodium reabsorption at multiple sites of the nephron. The response of this tubular renin-angiotensin system to stepwise changes in dietary sodium was investigated in 2 mouse strains, the sodium-sensitive inbred C57BL/6 and the sodium-resistant CD1 outbred. Plasma angiotensinogen was not affected by sodium regimen, whereas plasma renin increased 2-fold under low sodium. In both strains, the variation in urinary parameters did not parallel the changes observed in plasma. Angiotensinogen and renin excretion were significantly higher under high sodium than under low sodium. Water deprivation, by contrast, induced significant activation in the tubular expression of angiotensinogen and renin. C57BL/6 exhibited significantly higher urinary excretion of angiotensinogen than did CD1 animals under both conditions of sodium intake. The extent to which these urinary parameters reflect systemic or tubular responses to challenges of sodium homeostasis may depend on the relative contribution of sodium restriction and volume depletion.
Role of the
α
1D
-
Adrenegric Receptor in the Development of Salt-Induced Hypertension
Authors: Tanoue Akito , Koba Masahiro , Miyawaki Shigeki , Koshimizu Taka-aki , Hosoda Chihiro , Oshikawa Sayuri , Tsujimoto Gozoh
Published: July 2002

In an attempt to elucidate whether there is a specific α
1
-adrenergic receptor (α
1
-AR) subtype involved in the genesis or maintenance of hypertension, the α
1D
-AR subtype was evaluated in a model of salt-induced hypertension. The α
1D
-AR–deficient (α
1D
−/−
) and control (α
1D
+/+
) mice (n=8 to 14 in each group) were submitted to subtotal nephrectomy and given 1% saline as drinking water for 35 days. Blood pressure (BP) was monitored by tail-cuff readings and confirmed at the end point by direct intraarterial BP recording. The α
1D
−/−
mice had a significantly (
P
=0.0004) attenuated increase in BP response in this protocol (baseline 94.6±2.8 versus end point 107.4±4.5 mm Hg) compared with that of their wild-type counterparts (α
1D
+/+
), from a baseline 97.4±2.9 to an end point 139.4±4.5 mm Hg. Seven of 15 α
1D
+/+
mice died with edema, probably owing to renal failure, whereas 14 of 15 α
1D
−/−
mice were maintained for 35 days. Body weight, renal remnant weight, and residual renal function were similar in the 2 groups, whereas the values of plasma catecholamines (epinephrine, norepinephrine, and dopamine) were higher in α
1D
+/+
than in the α
1D
−/−
mice. These data suggest that α
1D
-AR plays an important role in developing a high BP in response to dietary salt-loading, and that agents having selective α
1D
-AR antagonism could have significant therapeutic potential in the treatment of hypertension.
Genome Scans for Blood Pressure and Hypertension
Authors: Hunt Steven C. , Ellison R. Curtis , Atwood Larry D. , Pankow James S. , Province Michael A. , Leppert Mark F.
Published: July 2002

This study presents genome scans for hypertension and blood pressures from 2959 individuals in 500 white families from the National Heart, Lung, and Blood Institute Family Heart Study. Genome scans were performed with different methods of handling the 27% of individuals taking antihypertensive medications. Variance components LOD scores were estimated by assigning medicated hypertensive individuals (1) to have a blood pressure of 140/90; (2) to be missing; and (3) to have a randomly assigned systolic blood pressure between 140 and 160 (N[150,5] distribution) and diastolic blood pressure between 90 and 100 mm Hg (N[95,2.5] distribution). There were 5 regions with heterogeneity LOD scores ≥2.0 for hypertension (unadjusted for multiple models): 2.8 on chromosome 1 (192 cM), 2.6 on chromosome 7 (58 cM), 2.0 on chromosome 7 (127 cM), 2.4 on chromosome 12 (83 cM), and 2.4 on chromosome 15 (103 cM). Diastolic blood pressure had no LOD scores ≥2.0. Only chromosome 6 showed linkage for systolic blood pressure, with a LOD score of 3.3 at 88.7 cM from the initial randomization. Multiple randomizations of medicated subjects’ systolic blood pressures yielded a mean LOD score of 2.8±0.4, whereas setting medicated systolic blood pressures to 140 mm Hg yielded a LOD score of 3.3. Excluding the medicated individuals or using their treated blood pressures reduced the LOD scores to 0.8 and 1.3, respectively, indicating the importance of including the extremes of quantitative trait distributions in linkage analyses. These results overlap other published scans, particularly regions on chromosomes 1 and 6, which have been implicated in familial combined hyperlipidemia.
Differential Expression of Adenosine Receptors in Human Endothelial Cells
Authors: Feoktistov Igor , Goldstein Anna E. , Ryzhov Sergey , Zeng Dewan , Belardinelli Luiz , Voyno-Yasenetskaya Tatyana , Biaggioni Italo
Published: July 2002

Adenosine has been reported to stimulate or inhibit the release of angiogenic factors depending on the cell type examined. To test the hypothesis that differential expression of adenosine receptor subtypes contributes to endothelial cell heterogeneity, we studied microvascular (HMEC-1) and umbilical vein (HUVEC) human endothelial cells. Based on mRNA level and stimulation of adenylate cyclase, we found that HUVECs preferentially express A
2A
adenosine receptors and HMEC-1 preferentially express A
2B
receptors. Neither cells expressed A
1
or A
3
receptors. The nonselective adenosine agonist 5′-
N
-ethylcarboxamidoadenosine (NECA) increased expression of interleukin-8 (IL-8), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in HMEC-1, but had no effect in HUVECs. In contrast, the selective A
2A
agonist 2-
p
-(2-carboxyethyl)phenylethylamino-NECA (CGS 21680) had no effect on expression of these angiogenic factors. Cotransfection of each type of adenosine receptors with a luciferase reporter in HMEC-1 showed that A
2B
receptors, but not A
1
, A
2A
, or A
3
, activated IL-8 and VEGF promoters. These effects were mimicked by constitutively active αG
q
, αG
12
, and αG
13
, but not αG
s
or αG
i1-3
. Furthermore, stimulation of phospholipase C indicated coupling of A
2B
receptors to G
q
proteins in HMEC-1. Thus, differential expression of adenosine receptor subtypes contributes to functional heterogeneity of human endothelial cells. A
2B
receptors, predominantly expressed in human microvascular cells, modulate expression of angiogenic factors via coupling to G
q
, and possibly via G
12/13
.
Effects of Angiotensin II Infusion on the Expression and Function of NAD(P)H Oxidase and Components of Nitric Oxide/cGMP Signaling
Authors: Mollnau Hanke , Wendt Maria , Szöcs Katalin , Lassègue Bernard , Schulz Eberhard , Oelze Mathias , Li Huige , Bodenschatz Martin , August Michael , Kleschyov Andrei L. , Tsilimingas Nikolaus , Walter Ulrich , Förstermann Ulrich , Meinertz Thomas , Griendling Kathy , Münzel Thomas
Published: July 2002

Angiotensin II infusion causes endothelial dysfunction by increasing NAD(P)H oxidase-mediated vascular superoxide production. However, it remains to be elucidated how in vivo angiotensin II treatment may alter the expression of the gp91
phox
isoforms and the endothelial nitric oxide synthase (NOS III) and subsequent signaling events and whether, in addition to the NAD(P)H oxidase, NOS III contributes to vascular superoxide formation. We therefore studied the influence of in vivo angiotensin II treatment (7 days) in rats on endothelial function and on the expression of the NAD(P)H oxidase subunits p22
phox
, nox1, nox4, and gp91
phox
and NOS III. Further analysis included the expression of NO-downstream targets, the soluble guanylyl cyclase (sGC), the cGMP-dependent protein kinase I (cGK-I), and the expression and phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) at Ser239 (P-VASP). Angiotensin II caused endothelial dysfunction and increased vascular superoxide. Likewise, we found an increase in vascular protein kinase C (PKC) activity, in the expression of nox1 (6- to 7-fold), gp91
phox
(3-fold), p22
phox
(3-fold), NOS III mRNA, and protein. NOS-inhibition with
N
G
-nitro-
l
-arginine decreased superoxide in vessels from angiotensin II-treated animals, compatible with NOS-uncoupling. Vascular NO assessed with electron paramagnetic resonance was markedly reduced. Likewise, a decrease in sGC-expression and P-VASP levels was found. In vivo PKC-inhibition with chelerythrine reduced angiotensin II-induced superoxide production and markedly inhibited upregulation of NAD(P)H oxidase subunits. We therefore conclude that angiotensin II-induced increases in the activity and the expression of NAD(P)H oxidase are at least in part PKC-dependent. NADPH oxidase-induced superoxide production may trigger NOS III uncoupling, leading to impaired NO/cGMP signaling and to endothelial dysfunction in this animal model. The full text of this article is available at http://www.circresaha.org.
Transcriptional Regulation of Vertebrate Cardiac Morphogenesis
Authors: Bruneau Benoit G.
Published: July 2002

Transcription factors can regulate the expression of other genes in a tissue-specific and quantitative manner and are thus major regulators of embryonic developmental processes. Several transcription factors that regulate cardiac genes specifically have been described, and the recent discovery that dominant inherited transcription factor mutations cause congenital heart defects in humans has brought direct medical relevance to the study of cardiac transcription factors in heart development. Although this field of study is extensive, several major gaps in our knowledge of the transcriptional control of heart development still exist. This review will concentrate on recent developments in the field of cardiac transcription factors and their roles in heart formation.
Cardiac-Specific IGF-1 Expression Attenuates Dilated Cardiomyopathy in Tropomodulin-Overexpressing Transgenic Mice
Authors: Welch Sara , Plank David , Witt Sandra , Glascock Betty , Schaefer Erik , Chimenti Stefano , Andreoli Anna Maria , Limana Federica , Leri Annarosa , Kajstura Jan , Anversa Piero , Sussman Mark A.
Published: July 2002

To test the hypothesis that early interventional treatment with insulin-like growth factor-1 (IGF-1) alleviates subsequent development of dilated cardiomyopathy, cardiac-specific IGF-1 expression was introduced by selective cross-breeding into a transgenic mouse model of heart failure that displays phenotypic characteristics of severe dilation. Hemodynamic, structural, and cellular parameters of the heart were compared between nontransgenic, tropomodulin-overexpressing cardiomyopathic, and the hybrid tropomodulin/IGF-1-overexpressing mice. Beneficial effects of IGF-1 were apparent by multiple indices of cardiac structure and function, including normalization of heart mass, anatomy, hemodynamics, and apoptosis. IGF-1 expression also acted as a proliferative stimulus as evidenced by calculated increases in myocyte number as well as expression of Ki67, a nuclear marker of cellular replication. Cellular analyses revealed that IGF-1 inhibited characteristic cardiomyocyte elongation in dilated hearts and restored calcium dynamics comparable to that observed in normal cells. Collectively, these results provide novel information regarding the ability of IGF-1 to inhibit progression of cardiomyopathic disease in a defined model system and suggest that heart failure may benefit from early interventional IGF-1 treatment.
PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes
Authors: Marx Nikolaus , Kehrle Bettina , Kohlhammer Klaus , Grüb Miriam , Koenig Wolfgang , Hombach Vinzenz , Libby Peter , Plutzky Jorge
Published: July 2002

Abstract—

Activation of T lymphocytes and their ensuing elaboration of proinflammatory cytokines, such as interferon (IFN)-γ, represent a critical step in atherogenesis and arteriosclerosis. IFNγ pathways also appear integral to the development of transplantation-associated arteriosclerosis (Tx-AA), limiting long-term cardiac allograft survival. Although disruption of these IFNγ signaling pathways limits atherosclerosis and Tx-AA in animals, little is known about inhibitory regulation of proinflammatory cytokine production in humans. The present study investigated whether activators of peroxisome proliferator-activated receptor (PPAR)α and PPARγ, with their known antiinflammatory effects, might regulate the expression of proinflammatory cytokines in human CD4-positive T cells. Isolated human CD4-positive T cells express PPARα and PPARγ mRNA and protein. Activation of CD4-positive T cells by anti-CD3 monoclonal antibodies significantly increased IFNγ protein secretion from 0 to 504±168 pg/mL, as determined by ELISA. Pretreatment of cells with well-established PPARα (WY14643 or fenofibrate) or PPARγ (BRL49653/rosiglitazone or pioglitazone) activators reduced anti-CD3-induced IFNγ secretion in a concentration-dependent manner. PPAR activators also inhibited TNFα and interleukin-2 protein expression. In addition, PPAR activators markedly reduced cytokine mRNA expression in these cells. Such antiinflammatory actions were also evident in cell-cell interactions with medium conditioned by PPAR activator-treated T cells attenuating human monocyte CD64 expression and human endothelial cell major histocompatibility complex class II induction. Thus, activation of PPARα and PPARγ in human CD4-positive T cells limits the expression of proinflammatory cytokines, such as IFNγ, yielding potential therapeutic benefits in pathological processes, such as atherosclerosis and Tx-AA.
Arterial Ultrastructure Influences Transport of Locally Delivered Drugs
Authors: Hwang Chao-Wei , Edelman Elazer R.
Published: July 2002

An incomplete understanding of the transport forces and local tissue structures that modulate drug distribution has hampered local pharmacotherapies in many organ systems. These issues are especially relevant to arteries, where stent-based delivery allows fine control of locally directed drug release. Local delivery produces tremendous drug concentration gradients and although these are in part derived from transport forces, differences in deposition from tissue to tissue imply that tissue ultrastructure also plays an important role. We measured the equilibrium drug uptake and the penetration and diffusivity of dextrans (a model hydrophilic drug similar to heparin) and albumin in orthogonal planes in arteries explanted from different vascular beds. We found significant variations in drug distribution with geometric orientation and arterial connective tissue content. Drug diffusivities parallel to the connective tissue sheaths were one to two orders of magnitude greater than across these sheaths. This diffusivity difference remained relatively constant for drugs up to 70 kDa before decreasing for larger drugs. Drugs also distributed better into elastic arteries, especially at lower molecular weights, with almost 66% greater transfer into the thoracic aorta than into the carotid artery. Arterial drug transport is thus highly anisotropic and dependent on arterial tissue content. The role of the local composition and geometric organization of arterial tissue in influencing vascular pharmacokinetics is likely to become a critical consideration for local vascular drug delivery.
Exercise Improves Postischemic Cardiac Function in Males but Not Females
Authors: Paroo Zain , Haist James V. , Karmazyn Morris , Noble Earl G.
Published: July 2002

Exercise is a physiological inducer of the cardioprotective heat shock protein, Hsp70. The putative biological events involved in signaling this response exhibit sexual dimorphism. Thus, it was hypothesized that exercise-mediated induction of Hsp70 would demonstrate sex specificity. After treadmill running, male rats exhibited 2-fold greater levels of cardiac Hsp70 relative to the levels in gonadally intact female rats (
P
<0.001). Ovariectomized female rats exhibited exercise-mediated induction of Hsp70 similar to that observed for male rats, and estrogen treatment in these female rats reversed this effect (
P
<0.001). Attenuation of Hsp70 signaling by estrogen was non–receptor-mediated, possibly involving a cellular membrane–stabilizing mechanism of action. The physiological importance of this sex-specific hormone-mediated stress response is underscored by the disparity in functional adaptation in response to exercise between male rats and female rats. Exercise markedly improved postischemic left ventricular developed pressure, the maximal rate of contraction, and maximal rate of relaxation, and it reduced left ventricular end-diastolic pressure in male rats (
P
<0.001). No such benefit of exercise was observed in intact female rats. A causal role for Hsp70 in this sex-specific cardioprotective adaptation was indicated, inasmuch as ablation of Hsp70 induction with antisense oligonucleotides designed against Hsp70 transcripts attenuated improvement in the recovery of cardiac function in exercised male rats (
P
<0.05). Thus, the sex-specific hormone-mediated Hsp70 response to exercise results in cardioprotective adaptation, preferentially in male rats relative to female rats. These findings suggest that exercise may be more important for males than for females in defending against the effects of heart disease and offer a novel manner by which males may reduce the sex gap in susceptibility to adverse cardiac events.